Why an Adaptive Response to Systemic Dysfunction, Rather than Cholesterol, is the Prime Driver of Cardiovascular Disease
Before we dive into the
mechanisms of atherosclerosis and those factors that influence them, some time
must be spent examining the history and value of LDL cholesterol as a
predictive measure of future cardiovascular disease. First though - to be clear
about terminology, please note that terms like “LDL” and “cholesterol” are
often used casually and interchangeably. I want to define some relevant terms,
as it will become increasingly important that the differences are well
understood.
· Cholesterol
is a waxy organic compound belonging to a class of molecules known as sterols.
Cholesterol is critical to cell membrane function and structure and is a
precursor to Vitamin D, various hormones, and bile acid, among other functions.
Cholesterol is hydrophobic, meaning it doesn’t interact well with water, and
must therefore be carried in the blood by lipoproteins.
· Lipoproteins are particles comprised mostly of proteins and
phospholipids, which are special lipid molecules with a phosphate. The primary
role of lipoproteins in the body is to move, through the blood, molecules that
cannot otherwise travel on their own, most famously cholesterol and
triglycerides. It is important to recognize that lipoproteins are not a biological
accident or a simple marker of health. They perform a critical role in the body,
that defines both their mechanics and their relationship to disease risk.
· Low-Density
Lipoprotein (LDL) is the most
“famous” of the lipoproteins, because it carries most of the cholesterol in
your blood at any given time. It is important to note that LDL itself is not
cholesterol, but one of many lipoprotein carrier molecules in your body.
· LDL-Cholesterol
(LDL-C) is a measure of the total
cholesterol being carried by LDL particles in your blood at any given time.
This is the measurement commonly seen on a standard lipid panel, and what
people are almost always referring to when they say “bad cholesterol” or “LDL.”
While the term “LDL” is used casually to refer to LDL-cholesterol, any
reference in this piece will use “LDL” to refer to the particles themselves and
“LDL-C” to refer to the measured cholesterol being carried by those particles.
History and Relevance of LDL-C
History of Cholesterol as a Health Marker
The history of cholesterol as the presumed driver of
atherosclerosis dates back some 70+ years, to autopsies of soldiers that
discovered often significant plaque deposits in their young arteries. These
plaques contained, among other things, cholesterol. There of course could be no
evidence from these autopsies what was actually causing the observed
atherosclerosis but, in conjunction with Ancel Key’s theory that fat
consumption led to both elevated blood cholesterol and increased heart disease
risk, cholesterol itself seemed like a prudent guess. I will in fact argue that
heavy smoking rates, a potent source of oxidative stress, were the key
factor instead.
What followed from these observations were the first
prospective studies on blood cholesterol levels and future cardiovascular
disease (CVD) and death. By far the most famous of these, the study that really
launched the lipid-heart hypothesis, was the Framingham Heart Study. In 1957,
the results of the first 4 year follow-up of middle-age men were released,
demonstrating a pronounced relationship between very high total cholesterol and
future heart disease.1,2 And to be clear, I do mean “very high.” This study predates our
ability to assess cholesterol subfractions (ie. LDL-C separate from HDL-C separate from triglycerides) and instead only measures total cholesterol. Only total
cholesterol levels above 260 mg/dl were associated with an increase in CVD.
To loosely translate that value into more a modern
LDL-C context, lets estimate HDL-C and triglycerides at the standard cut points
of 40 mg/dl and 150 mg/dl respectively. This would imply an LDL-C level of
approximately 190 mg/dl. This isn’t hyper-accurate of course, but because HDL-C
and triglycerides are strongly inversely correlated, its difficult for their
combined contribution to differ too much from that estimate. Another paper I’ll
reference later fits this estimation quite closely, correlating an average LDL-C
of 135 mg/dl to a total cholesterol of 202 mg/dl.3 The point is, we are absolutely talking about individuals with LDL-C
levels in the upper 100s or even above 200 mg/dl. Critically, this means that
those with LDL-C values in the 140s, 150s, 160s were not suffering
increased CVD compared to those with lower LDL-C values. Despite this being the
most relevant study in establishing the apparent relationship between cholesterol
and heart disease, the findings are not particularly consistent with today’s recommendations
that LDL-C levels should be below 100 mg/dl for the prevention of CVD.
The other piece of relevant formative history that we
will touch on now, and later in another context, is the Minnesota Coronary
Experiment. This was an extensive “gold-standard” study designed to test the
idea that replacing saturated animal fats with highly unsaturated industrial oils
would lead to lower cholesterol levels and reductions in CVD. Indeed, while LDL-C
was stable in the saturated fat group, it dropped significantly in the
unsaturated fat group. However, this decrease in LDL-C was in fact associated with
marked increases in mortality rates. However, only the decrease in LDL-C
was immediately published, allowing the experiment to play a pivotal role in
solidifying the notion that saturated fat and cholesterol consumption drives
blood cholesterol levels and (so the logic went) cardiovascular death.4,5
LDL-C as the Prime Driver of Cardiovascular Disease
For the rest of this piece, I’m going to frequently
quote from and reference the European Atherosclerosis Society’s two consensus statements
on atherosclerotic cardiovascular disease.6,7 The EAS is a world-leading authority on atherosclerosis and I will be
using their words as a proxy for the cardiology/medical community at large. They
claim, in no uncertain terms that the evidence “unequivocally establishes that
LDL causes atherosclerotic cardiovascular disease.” They go on to state time
and time again that this occurs in a “dose-dependent” manner. Put simply, the
original consensus statement advances the notion that low LDL-C is good, some
more is bad, and even more is worse. This truth is, as they describe it, unequivocal.
I struggle very much to find support for this unambiguous
proclamation. Does an association between LDL-C and CVD exist? Generally, yes,
it does. That Framingham result is real, for example, as are other prospective
studies assessing the same thing.8,9 However, an association is not evidence of a causal relationship, as
we will explore later. Those studies are fewer and weaker than you might imagine
and, more importantly, its almost trivially easy to find other chronic health
markers that predict CVD more strongly than LDL-C.
LDL-C Vs Other Chronic Health Markers
Framingham Offspring Analysis
While we’ve only touched on the initial findings, the Framingham Heart Study is actually a decades-long undertaking, with a wide range of “offspring” and follow-up papers in the years that followed the initial publication. Below are two images from one such paper, stratifying CVD risk by lipid subfractions – LDL-C, HDL-C, and triglycerides.10 Again, to be clear, there does exist some association between increasing LDL-C and increasing CVD rates. However, as can be clearly seen, the CVD rates are associated more strongly with the other markers of metabolic health (further references to “metabolic markers” in this section is shorthand for both HDL-C and triglycerides).
Now obviously that’s only one study, so we need to look at some more. Below is the graph from another prospective study of lipids and CVD rates, with HDL-C and triglyceride/HDL-C ratio both strongly predicting CVD development while LDL-C fails to reach statistical significance.11 Again, there is an obviously a trend with LDL-C that we’ll explore later, but a trend that pales in comparison to other markers is quite a far cry from unambiguous proof of dose-dependent causality.
How about another prospective study that spent 16 years tracking LDL-C, blood pressure, and CVD risk.12 Firstly, this is one of those “weaker than you’d imagine” studies I alluded to above, as no level of LDL-C actually reached a significant association with increased CVD rate. There was certainly a trend in that direction, but even among those individuals with LDL-C levels above 190mg/dl it only that – a weak trend, not reaching statistical significance. Compare that now to blood pressure, the other half of the study. In this case, hypertension and CVD rates demonstrated a strong, statistically significant association (and dose-dependent too!). In fact, even mild-moderate levels of hypertension predicted future CVD better than the highest levels of LDL-C. Its worth noting, perhaps, that blood pressure predicted future CVD a bit better than did total cholesterol in the initial Framingham Study as well. Once again, these findings are incompatible with the idea that dose-dependent LDL is the primary cause of cardiovascular disease.
*Side note on these markers – these are good tests
to ask your doctor about, but note the values on these graphs. You will absolutely
get labs that report <400 GlycA and <10 hsCRP as normal values, because they
don’t indicate an immediate or severe danger. DO NOT mistake results along the
lines of 350 or 2.5 as healthy even if they are flagged as “normal.”
Some quick hitters now, starting with a study finding remnant
cholesterol and triglycerides to outperform LDL-C:
In overweight or obese
subjects at high cardiovascular risk, levels of triglycerides and remnant-C,
but not LDL-C, were associated with cardiovascular outcomes independent of
other risk factors.13
And one that found LDL particle size (small, dense LDL
particles) to be far more relevant than LDL-C:
“Even in individuals considered to be at low
cardiovascular risk based on their LDL-C levels, sdLDL-C predicted risk for
incident CHD (hazard ratio, 1.61; 95% confidence interval, 1.04-2.49).”14
This study did not only find LDL-C to be inferior to
the ApoB/LDL-C ratio, but in fact those with poorer ratios and greater disease
rates had lower LDL-C:
“Elevated LDLapoB/LDLC
(calculated and measured) ratios were significantly and independently
associated with increased cardiovascular mortality in the entire cohort (fourth
vs. first quartile: hazard ratio (95% confidence interval) = 2.07 (1.53–2.79))
and in statin-naïve patients”15
Remnant cholesterol is that which is “left over” after
triglycerides fail to be properly taken up by fat and muscle cells. ApoB is a structural
component of LDL particles and a close proxy for LDL particle count. Thus, the the
ApoB/LDL-C ratio is indicative of the cholesterol contained within each
particle, in turn indicative of particle size. What do remnant cholesterol, triglycerides,
ApoB/LDL-C ratio, and small LDL particle size all have in common? They highlight
poor metabolic health, with poor values all manifesting downstream of decreased
metabolic efficiency.
Last short round of studies, to touch on glucose and
insulin. The triglyceride-glucose index, incorporating both triglycerides and glucose,
and shows a statistically significant and dose-dependent relationship with CVD16:
C-Peptide, a marker of long-term insulin levels, is strongly
(and, again, in a dose-dependent fashion) linked to CVD in this study:
“In men, compared with
the lowest quartile of the serum C-peptide level, the relative risk was 1.75,
2.79, and 3.07 for the upper three quartiles of the serum C-peptide level. The
relative risk was 1.60, 2.61, and 3.67 for women”17
And here’s data from the Women’s Health Initiative, finding
that LP-IR (a marker of insulin resistance) was some 14 times more strongly linked
to CVD. Diabates, smoking, obesity, blood pressure, triglycerides, and
metabolic syndrome each outperformed LDL-C as well:
“In this cohort study,
diabetes and insulin resistance, in addition to hypertension, obesity, and
smoking, appeared to be the strongest risk factors for premature onset of CHD”18
Ok, this is hardly an exhaustive list and its still
getting very wordy. I wanted to at least touch on one study for most common
metabolic and chronic health markers – HDL, triglycerides, blood pressure, GlycA,
CRP, markers of insulin resistance, LDL particle size, remnant cholesterol –
that commonly outperform LDL-C in associating with the development of future cardiovascular
disease. This is, simply put, incompatible with the notion that LDL is the causal
driver of cardiovascular disease. If that were the case, there should not a
wide array of metrics that can, at least sometimes, better predict CVD development.
It would not be the case that the relationship between LDL-C and CVD can disappear
when you add other measures. It should be the case that LDL-C predicts
CVD in a reliable fashion independent of any other condition or factor. But
that simply isn’t true - The position that LDL unequivocally causes CVD in a
dose-dependent manner is difficult to support with prospective data.
LDL-C and All-Cause Mortality
A quick note on LDL-C and all-cause mortality. Everything
above was concerned only with future CVD development, not overall health
outcomes or death. It is an extremely consistent finding that low LDL-C,
rather than high, is associated with greater mortality rates.19–26 These findings should, I think, at the very least seriously
call into question the goal of aggressive lipid lowering in those without
existing cardiovascular disease. Below are the raw and adjusted mortality rates
by LDL-C levels for American adults from the ongoing National Health and
Nutrition Examination Survey:27
The Atherosclerotic Process
*You can start here if you’re looking to skip 2,500
words on LDL-C’s underwhelming relationship with CVD
Hopefully I’ve established at least some degree of
doubt that LDL-C that is the singular, or even the most prominent, driver of cardiovascular
disease. It passes neither the “unequivocal” nor the “dose-dependent” conditions,
and I’d like now to address the “causal” condition as well.
We’re going to work backwards a little bit here, first
addressing the actual atherosclerotic cascade and then working backwards to
address the factors that influence the initiating steps. It has historically
been the case, I think, that the consensus on LDL’s role in driving
atherosclerosis has been a bit laissez-faire – that basically high LDL-C means LDL
particles will inevitably filter across the endothelium (the lining,
effectively) of the blood vessel and become stuck there. Indeed, the EAS agrees
with me on this point, pointing out that “a considerable body of evidence in
recent years has challenged the concept that movement of LDL occurs by passive
filtration (i.e. as a function of particle size and concentration) across a
compromised endothelium of high permeability.”6
As they proceed to acknowledge, it is actually the
transcytosis (an active and deliberate process of transferring molecules across
a cell) of LDL particles that appears overwhelmingly responsible, and that “LDL
transport across the endothelium in the systemic circulation seems to be LDL
receptor-independent.” The LDL receptor (LDLr) is basically what it sounds
like, a protein on the surface of nearly every type of cell in the body that
serves to “take in” LDL particles by endocytosis. This is, basically, how cells
can take in and utilize the cholesterol contained with the LDL particle. The greatest
density of LDLr, by far, is found on liver cells, where it serves to take LDL
particles out of circulation.28 But endocytosis by LDLr is very different than transcytosis, a process
with a number of other relevant players.
Major receptor molecules involved in transcytosis include
the following:
·
Lectin-like
Ox-LDL receptor-1 (LOX-1) – a cell-surface
receptor located in blood vessel endothelium named for its affinity in binding,
most notably, oxidized LDL particles (those that have suffered some degree of
damage by oxidative/inflammatory processes). Other modified particles targeted
by LOX-1 include those damaged via glycation. LOX-1 acts by recognizing,
binding, and internalizing target particles.29–31
·
CD36 – another scavenger protein found in the blood vessel
endothelium, that can bind various lipoprotein classes. Some studies indicate
that CD36 only binds oxLDL, but not native LDL particles. Other studies note that
CD36 is indeed able to bind native LDL, but has a much stronger binding
affinity for oxLDL and VLDL (the LDL precursor that carries the aforementioned remnant
cholesterol).32–34
·
SR-B1 – a membrane protein found throughout the body, most
notable for its function as an HDL receptor. However, SR-B1 can also bind LDL
particles for transcytosis. SR-B1 preferentially binds HDL and oxLDL, with one
study suggesting that it will not bind native LDL in normal conditions and
another suggesting that increases in HDL particles serve to take preference
over LDL and effectively prevent the transcytosis of LDL particles.35–37
Many other inflammatory, immune, and signaling
molecules are relevant as well:
·
Cytokines – a class of proteins involved in immune/inflammatory
signaling. Tumor Necrosis Factor (TNF) is one relevant example
· Macrophages/Monocytes – White blood cells involved in the immune response to LDL
particles in the endothelial space. They internalize and degrade the targeted
LDL particles38–40
·
Vascular Cell
Adhesion Molecule 1 (VCAM-1) – an immune
protein that can be expressed on blood vessel endothelial cells. As the name
suggests, VCAM-1 contributes to the atherogenic pathway by helping to recruit
and bind immune cells to the site of endothelial insult.41,42
·
Intercell Adhesion
Molecule 1 (ICAM-1) – another adhesion
protein expressed in inflammatory and disease states, much like VCAM-143
·
Monocyte
Chemoattractant Protein 1 (MCP-1) – a
cytokine instrumental in regulating monocyte migration to and infiltration
within vessel endothelium 39,44
·
Nuclear Factor
Kappa Beta (NF-kB) – an immune-modulating
protein involved in the inflammatory process of many disease states.
Contributes to cardiovascular disease through upregulation of VCAM-1, MCP-1,
etc.42,45
·
NADPH Oxidase – a membrane-bound enzyme that that contributes to the
atherosclerotic inflammatory process by catalyzing the formation of reactive
oxygen species (free radicals)46,47
·
Nitric Oxide –
a gaseous signaling molecule instrumental
in regulating blood pressure and vascular tone. Also involved in the suppression
of platelet aggregation and vascular lesion development. Decreased NO
availability and/or function are associated with atherosclerotic disease
progression.48–51
Significant interplay exits between each of these
receptor-, inflammatory-, and signaling molecules in the process of
atherosclerosis. For example, the binding of oxidized LDL (OxLDL) by LOX-1 has several
downstream effects, including the activation of the typically dormant NADPH
Oxidase.46,47 Another particularly critical factor is the upregulation of NF-kB.38,52,53 This in turn leads to upregulation of various cytokines and adhesion
molecules, such as VCAM-1 and MCP-1.40,42,45 VCAM/MCP-mediated attraction draws macrophages to the site of LDL
particle entrapment, where they internalize and degrade the LDL particles in
the formation of something known as a foam cell.44,54,55 Foam cells, effectively the early stage of atherosclerosis, themselves
secrete further inflammatory cytokines and macrophage retention factors that
promote further LDL uptake and discourage migration of the foam cell away from
the site of initial LDL entrapment.56–58 This in turn promotes the proliferation of vascular smooth muscle
cells that can form a fibrous cap over the site of foam cell accumulation.59–61 This is, essentially, the process of plaque formation.
The contributions of inflammatory mediators, adhesion molecules, and the like are widely recognized and not in dispute. However, mainstream assumptions surrounding initiating factors are still typically rooted in the prevalence of LDL particles rather than the nature of those particles or the overall vascular environment. Instead of passive influx of LDL particles into the endothelial space, emphasis is seemingly shifting towards a model based on a sort-of demand-driven transcytosis and damage to those engulfed particles only after they’ve been incorporated into the endothelium. It is important to recognize that native, nondamaged LDL particles are not typically recognized by scavenger receptors and taken up by macrophages at massively reduced rates or not at all.33,62–68 The EAS acknowledge as such:
“Whereas
the classic TG-poor LDL requires modification for efficient uptake by arterial
macrophages, remnant particles are taken up by members of the LDL receptor
family in their native state”6
*Note
that the ability of remnant particles to be taken up unmodified explains part
of the reason that high measured remnant cholesterol (and closely associated triglycerides)
is such a concern*
But recognizing that the immune response to LDL particles requires that these particles be in some way damaged does not explain the simultaneous position that the number of LDL particles is the driving factor. To reconcile those differences, we end up with a model that suggests the number of LDL particles is still what drives transcytosis, but that the requisite damage occurs in response to this uptake. But that simply adds extra steps to the original “dose-dependent” argument and leaves us right back where we started – if the number of LDL particles is the prime driver of LDL transcytosis and LDL modification, none of those studies listed earlier should exist. It should still be, by this logic, that all people with very high LDL are inevitably in the process of developing atherosclerosis. But of course this isn’t true – evidence of the dose-dependent casual nature of LDL isn’t particularly strong and disappears when metabolic health is accounted for. People with very high LDL and good metabolic health markers suffer less cardiovascular disease, not more.
So I think the key point in the initiation of atherosclerosis
is that modification of LDL particles occurs upstream of their entrapment. In
fact this seems unescapable in the context of the action of scavenger receptors
like LOX-1. LOX-1 is binding damaged lipoproteins and bringing them into the
cell. It doesn’t bind non-modified LDL particles, and would have no relevance
whatsoever if these healthy particles were otherwise entering the cells and
being damaged only once they were randomly selected for transcytosis.
How Does an LDL Particle Become Modified?
Unfortunately, while the above may explain the initiating
factors in atherosclerosis, it does nothing to explain the genesis of modified
LDL particles, why LDL-C retains a general association with CVD, or why
metabolic health matters to such a great degree. For that, we have to take a
couple steps back.
Lipid mechanics is a topic I’ve written about at great length, so I’ll try to summarize as briefly as possible and point you to this series or this paper if you’d like a deeper dive. Declining metabolic efficiency and declining metabolic health essentially happen by the following steps:
- This is what drives increases in levels of triglycerides and remnant cholesterol
3. Increased VLDL-triglyceride levels dictate that excess triglycerides must return to the liver to be offloaded there
- This decreases the cholesterol in HDL particles, depressing measured HDL-C values
- This increases the amount of cholesterol in VLDL particles returning to the liver
- LDL particles that traded away cholesterol for triglycerides now shrink in size as they offload triglycerides
- LDL particles have a lifespan 20-30 times longer than VLDL particles, allowing them to serve as trade partner several times, resulting in progressively smaller LDL particles
- VLDL particles reenter the blood stream as triglyceride-poor LDL particles
- These VLDL and subsequent LDL particles all contain cholesterol, and additional cholesterol after trading away triglycerides, ultimately leading to elevated LDL-C levels
That’s the overview of dysfunctional lipid mechanics.
I’ve bolded the changes in lipid profiles you would expect to see when this
happens. These markers – low HDL-c, high triglycerides, high VLDL/remnant
cholesterol, small LDL particles – occur largely in concert with one another and
are a highly concerning indicator of poor metabolic function. As you can see,
this eventually leads to an increase in LDL-C levels as well. This is not the
only manner by which LDL-C can be elevated, but it is the most common and how
LDL-C comes to be associated with cardiovascular disease.
But! That still doesn’t tell you how an LDL particle
becomes modified and potentially destined for scavenger targeting and
atherosclerotic contribution. The most important direct factor from the steps
outlined above is the genesis of small LDL particles. Small LDL particles are particularly
susceptible to oxidative damage.69,70 Additionally, they are far more prone to glycation, which occurs when
the hyperglycemia and insulin resistance typical of metabolic impairment helps
drive the nonenzymatic reaction of glucose with the free lysine groups ubiquitous
to LDL particles.71–78 This, however, is but one factor.
The Many Methods by Which Diet and Lifestyle Drive LDL
Modification and Transcytosis
At this point, we have still only set the table – modified
LDL particles are ripe for immune targeting, and metabolic dysfunction drives small
LDL particles that are prone to modification. To bring everything together, and
to delve into the evolutionary basis for such processes, further exploration of
the dysfunctional metabolic and vascular environments is needed.
Excess Carbohydrate Decrease Metabolic Health
I will of course clarify that “excess” is going to vary
from one person to another based on genetics, lifestyle, and other factors, but
the above statement is unequivocally true.
- It is intuitive, of course (and easily fits the narrative that fat drives disease) to believe that fat consumption increases triglycerides in the blood. However, this is untrue, as partially explained above. Instead, carbohydrates raise blood sugar and insulin levels, decreasing the expression of lipoprotein lipase (responsible for liberating triglycerides from VLDL) and preventing VLDL from delivering their triglycerides to the body. Additionally, excess glucose and a large percentage of fructose consumed all is converted to new triglycerides in the liver by the process known as de novo lipogenesis.79–82 Instead of a high-fat meal transiently increasing triglycerides, a meal with excess carbohydrates is liable to both increase triglycerides and prevent the body from dealing with them in a timely manner. This, repeated to excess and in conjunction with chronically increasing levels of insulin, creates an enduring elevation of measured triglycerides. This is, perhaps, the most thorough and consistent finding in all of nutrition science, with dozens of human trials confirming the result.82–118
- It is clear from the steps outlined above why and how triglyceride
and HDL-C levels are so tightly linked, as elevated triglycerides lead directly
to a reduction in HDL cholesterol levels. Unsurprisingly, then, a plethora of
studies have also confirmed the effect of excess carbohydrate consumption on
HDL-C depression.85,95,111–113,119–137 While triglycerides serve more as a marker of poor
metabolic health, we will see later the ways in which low HDL-C may be acutely detrimental.
- VLDL-C and remnant cholesterol should be clear at this point as well – reducing carbohydrate consumption reduces/improves VLDL-C levels.87,115,138–141
- Similarly, and perhaps most relevantly, a decrease in carbohydrate consumption also drives an increase in average LDL particle size and a decrease in the prevalence of small LDL particles.93,114,115,142–148
It should be unambiguous at this point, but to
summarize – reduced carbohydrate consumption routinely improves metabolic
health markers, including those that often correlate strongly with CVD, while simultaneously
discouraging the genesis of potentially dangerous small LDL particles.
Excess Carbohydrates Damage the Vascular Environment
A decrease in metabolic health is not the only, and
perhaps not even the most important, consequence of excess carbohydrate consumption
and the hyperglycemia and hyperinsulinemia that often follows. Factors related
to inflammation, LDL particle modification and entrapment, and vascular health
are impacted by carbohydrate consumption in the following ways:
· Increases in glycemic load, increased fructose
consumption, and decreased fat consumption have all been demonstrated to increase
OxLDL levels149–155
· Glycated proteins increase NF-kB signaling, elevate
blood pressure, and increase expression of oxidized LDL receptors156–165
· Hyperglycemia increases expression of LOX-1166–168
· Glycated LDL particles become an increased target for
scavenger receptors such as LOX-138,169–172
· Hyperglycemia and hyperinsulinemia increase expression
of the scavenger protein CD36173–180
· Hyperglycemia increases the expression of NF-kB and
the free-radical generating NADPH oxidase181–188
· Hyperglycemia alters transcription factors that affect
nitric oxide availability, decreasing nitric oxide levels49,155,189–192
· Hyperglycemia both damages and impairs rebuilding of the protective glycocalyx that lines the walls of the blood vessels193–197
Role of Fatty Acid Consumption in Oxidative Stress
While widespread glycemic modification of both lipoprotein particles and the overall vascular environment is an obvious cause for concern, it does not fully capture the ways in which diet may influence lipoprotein damage. Oxidative stress downstream of lipoprotein remodeling must also be considered.
The fatty acid composition of your diet absolutely influences the fatty acid composition of LDL particles (and other membranes in your body).198–204 This may seem obvious, as the phospholipids used to construct lipoprotein membranes are, broadly speaking, provided by the diet. This has been confirmed in several studies, but I’ll quote from one here:
“In
conclusion, the present data support the hypothesis that isolated dietary ALA,
EPA, and DHA intakes lead to differential enrichment in LDL due to
interconversion.”199
At this point, we probably need a brief chemistry lesson to ensure the difference in saturated and unsaturated fats is well understood. A fatty acid is effectively a chain of carbon molecules bound together, with hydrogens attached to each of the carbons. In simple terms, it is an unbreakable rule of chemistry that a carbon molecule always binds four times to its neighbors. Thus, in a fatty acid chain, a carbon may bind to each of its two carbon neighbors and to two hydrogens as well, for a total of four bonds.
The “saturated” part of saturated fat refers to a carbon chain that is fully saturated with hydrogens – each carbon is bound to two (except the last carbon, which binds three). An unsaturated fat, then, is one that does not contain a full complement of carbons. But this poses a problem of sorts, because each carbon still needs four bonds. What happens instead is that carbons without a second hydrogen will instead form a second bond (called a double bond) with its neighboring carbon, thus satisfying the requirement for four total bonds. A monounsaturated fat (MUFA) is a fatty acid with one such double bond, while a polyunsaturated fat (PUFA) has two, three, or even more double bonds. Crucially, the second bond in a double bond is not as strong as the first and is the bond most susceptible to damage in cases of inflammatory or oxidative stress. This is because, to quote a chemistry textbook, “the addition of carbon radicals to double bonds is energetically favorable.”205
The main takeaway is that highly unsaturated fatty
acids are susceptible to oxidative damage at the hands of free radicals/reactive
oxygen species that may degrade the fatty acid and generate unwanted
byproducts. This has been demonstrated in a number of studies.206–212 One such study extracted human LDL particles and exposed them to 24
hours of continuous oxidative stress, measuring the degree of degradation of
various fatty acid types. While saturated (4.7% degradation) and monounsaturated
fatty acids (5.4%) were largely resistant to degradation, polyunsaturated fatty
acids degraded at a much higher rate – 24.8%.209 Another study found the following concerning the common polyunsaturated
fat linoleic acid:
“Stepwise
multiple regression indicated that the primary predictor of oxidative
susceptibility of LDL was linoleic acid”207
And another, linking linoleic acid specifically to an
increased expression of LOX-1:
“LA
also led to a significant increase in LOX-1 gene expression…Finally, LA
enhanced, through LOX-1, oxLDL uptake by endothelial cells. Overall, these
results demonstrate that LA enhances endothelial LOX-1 expression”213
In short, it is highly unsaturated fatty acids in the phospholipid
membrane that are most likely to be damaged and targeted for uptake by scavengers
like LOX-1 and CD36. I do want to make a clarifying dietary point about PUFAs
in the diet though – I am not telling anyone to avoid all PUFAs. The omega-3
fatty acids found in fish, for example, are essential for health. Instead, I think
a very specific attention should be paid to industrial seed oils – soybean, safflower,
canola, grapeseed, sunflower, etc. – for a number of reasons. First is that
they typically contain higher levels of PUFAs and the less desirable omega-6 fatty acids, like linoleic acid, than almost anything else you could
ever consume. Second is that, unlike something like olive oil, they require a
very harsh heating and chemical extraction process to be made usable. This
process likely induces oxidative damage before even entering your body. Third
is specific to their danger as a cooking oil, which is well-known to generate
large amounts of free radicals and other toxic byproducts.214–222 It is specifically processed seed oils I would advise one to avoid in
the interest of limiting phospholipid oxidation.
On the Function of HDL and the Implications of its Reduction
Of all the negative CVD factors so far highlighted, one that deserves special attention due to its downstream effects is the role of HDL in cardiovascular health. HDL-C is widely recognized as and demonstrated to be an important marker of metabolic and chronic health. We know, definitively, that HDL-C levels are decreased by excess carbohydrate consumption, hyperglycemia, and impaired metabolic efficiency. However, its contribution to CVD risk is more than simply its status as a marker of overall metabolic health.
- SR-B1 Competition – As noted above, SR-B1 is most traditionally known for its role as an
HDL receptor. While SR-B1’s ability to bind undamaged LDL particles is unclear,
what does seem certain is the ability of increased HDL particle prevalence to preferentially
shut out the binding and transcytosis of LDL particles of any type, be they
damaged or not.
- Nitric Oxide Production - SR-B1 also serves another critical role in vascular health – binding of HDL to SR-B1 initiates a signaling cascade that increases production of highly beneficial nitric oxide.193,223
- Reverse Cholesterol Transport – Reserve cholesterol transport is the process by which cholesterol is removed from the body’s tissues and (primarily) returned to the liver. HDL is involved with transport of cholesterol to and from a wide variety of tissues and organs, but RCT most directly refers to HDL’s capacity to extract cholesterol from the foam cells that result from macrophage retention of modified LDL particles. We’re going to skip the technical details but, in effect, HDL particles can and do limit the capacity of the inflammatory macrophage response to generate lasting atherosclerotic plaques. The important note here is that both low levels of HDL particles and oxidized HDL particles lead to a reduced capacity of this reverse cholesterol transport process.224–227
- And a quick note on HDL particle count – HDL particle count is associated with decreased CVD, in part because of reduced RCT. Production of the primary HDL structural component, apolipoprotein A1, and thus production of new HDL particles, is driven by fat consumption.134,228–231 Unsurprisingly, higher fat consumption is associated with increased HDL particle count.93,142,232,233 A personal anecdote – my HDL-C levels drop by ~15mg/dl from my high-fat diet standard when engaged in multi-day fasting, despite similarly low triglyceride levels.
The Atherosclerotic Process in Summary
Rather than an LDL particle prevalence model that is
inconsistent with the sustained cardiovascular health in those with elevated
LDL-C but good metabolic markers, the model proposed here can be summarized as
such:
- Declining metabolic health generates common markers associated with negative cardiovascular and overall health outcomes – low HDL-C, high triglycerides, increased remnant cholesterol, insulin resistance, and decreased LDL particle size
- Impairment of metabolic health occurs with near uniformity in an environment of excess carbohydrate consumption and hyperglycemia
- Small LDL particles are uniquely susceptible to modification by excess glucose and, critically, are generated in a hyperglycemic environment that naturally leaves them exposed to such damage
- Hyperglycemia and oxidative stress combine with PUFA-rich LDL particles to generate a preponderance of modified LDL particles
- Scavenger molecules like LOX-1, CD36, and SR-B1 are responsible for the transcytosis of these particles, preferentially or exclusively binding oxidized or otherwise damaged LDL particles
- Both the transcytosis of modified LDL particles and the hyperglycemic/inflammatory environment stimulate the action of inflammatory and immune molecules such as TNF, NF-kB, VCAM-1, MCP-1, and macrophages.
- The actions of these immune processes encourage further retention of macrophages, which sequester modified LDL particles in the endothelial space
- The capacity of HDL particles to limit this process is reduced alongside lower HDL-C levels, driven by metabolic dysfunction
- The same metabolic dysfunction ultimately increases compensatory
VLDL production and downstream LDL-C levels, creating the general association between
rising LDL-C levels and the atherosclerotic process just described.
A Word on Lipid Lowering Therapies
I’m going to include a quick word on lipid-lowering
medications, lest anyone think I’m trying to ignore them.
Indeed statins decrease LDL-C considerably, typically alongside concurrent reductions in CVD rates. While that is used as evidence by many to support the notion that LDL causes CVD disease, I do not agree for a couple of reasons. One is that while statins can have a variety of both positive and negative non-lipid effect, some of these – notably an apparent anti-inflammatory benefit and an obvious increase in nitric oxide signaling – can, as we’ve seen, discourage CVD risk independent of LDL-C levels.234,235 The bigger reason is the manner by which statins reduce LDL-C levels – by increased reuptake of LDL particles. An LDL-C reduction of, say, 30% is achieved by the same 30% reduction in LDL particle count and therefore the same 30% decrease in damaged LDL particle count. The reduction is such particles would decrease aspects of atherosclerotic initiation, is obviously beneficial and, combined with the other beneficial effects listed above, can reasonably suggest a reduction in CVD rates independent of actual LDL-C levels. None of that is a statement for or against statins, only an expression of doubt that their capacity to improve some cardiovascular outcomes proves that cholesterol was responsible for the disease risk.
On the other hand, I might argue that a major study
demonstrating PCSK9 inhibitor Evolocumab’s (Repatha) ability to reduce LDL-C to
subhuman levels (30mg/dl) without making the slightest dent in cardiovascular deaths
might suggest that LDL is not unequivocally causal in a dose-dependent manner.236–238
An Evolutionary Explanation
I promised that this piece was going to explain atherosclerosis
as an evolutionary adaptation, and we’re finally getting to that point now. First,
consider the steps one would want to take to reduce each risk factor outlined
above and how that might influence dietary choices – The choices that improve
metabolic efficiency, retain or improve HDL levels and function, prevent the shrinking
of LDL particles, limit glycemic and oxidative modification of LDL particles,
limit expression of NADPH oxidase and NF-kB, limit the action of LOX-1 and
CD36, prevent SR-B1 from binding LDL particles, increase nitric oxide signaling,
and shift foam cell status away from macrophage retention and towards HDL cholesterol
efflux…are all the same choices. Simply the avoidance of highly glycemic and
oxidative environments, and of fatty acids highly susceptible to oxidative
modification, solves each of these problems.
I would argue that these issues are really only driven
by three classes of food. The first, refined and added sugars, is probably obvious
given our lengthy discussion of hyperglycemia. The second is grains, which have
just as great a glycemic effect as sugar, with little nutritional value to
offset it. And the third is, as previously mentioned, highly processed industrial
seed oils, which serve as the primary dietary source of both oxidized and oxidize-able
fatty acids. It would be very difficult to eat a diet consistent with the hyperglycemic,
inflammatory state that drives the atherosclerotic state without these foods.
It is critically important to the evolutionary argument
that these foods are not historically consistent with human consumption. Humans
and their ancestors have eaten animals, berries, nuts, and the like for
millions of years, but each of the foods described above are very recent introductions
to the human diet – an introduction far too recent to have evolved meaningful compatibility
with their consumption. Without their consumption, our ancestors would have had
relatively little concern for declining metabolic efficiency and hyperglycemia-induced
activation of inflammatory atherosclerotic factors.
Lets imagine a situation in which they might, though.
Perhaps finding a patch of berries would lead to reasonably extreme
consumption. This would be prudent, of course, as you wouldn’t want to make a habit
of passing up good food. What would happen? Well, in a transient sense,
everything I’ve been describing. To be clear, the body of a relatively healthy
person would handle the binge better than most modern people would. But,
basically, significant elevations in blood sugar would temporarily shift the
lipid profile towards elevated triglycerides, smaller LDL particles, and the
like. Significant increases in blood sugar might increase expression and
activity of inflammatory signaling molecules and transcytosis of LDL particles acutely
modified in a short-term hyperglycemic environment. All the things that happen chronically,
over and over and over again, in today’s population would happen here as well. The
big difference, of course, is the duration of the sub-optimal metabolic state
and the capacity to deal with it. Chronic metabolic efficiency would hardly be affected,
and lipid profiles would stabilize quickly after the berry buffet.
Critically, high baseline HDL levels would return to
normal in short order, retaining the capacity for reverse cholesterol transport.
This is in contrast with modern metabolically unhealthy persons, who suffer
chronic deficits of this process. This is another important piece of the evolutionary
puzzle – our ancestors would have not harmed their long-term capacity to “clean
up” the initial steps of the atherosclerotic process. As high-glycemic
consumption would have been far less frequent and far less severe than most people
are exposed to today, the vascular system of our ancestors may have been able
to effectively withstand intermittent or transient insults. The steps towards atherosclerotic
progression would have been minor, and much more easily dealt with, allowing
for much better long-term health. Essentially, it would have been “safe” to create
transiently dangerous metabolic and vascular environments that are typically
anything but transient today.
However, an explanation for why the atherosclerotic
process would have been historically safe is not the same thing as an explanation
for why it exists the way it does. For a process that occurs so commonly in modern
humans, it would not be unreasonable to imagine that there should be some reason
for it. While not an absolute requirement, the development of the vascular and atherosclerotic
systems in this way would suggest that these processes may have conferred some
kind historic advantage. It is very possible that those of our ancestors who
survived to have children and grandchildren did so in some part because this
manner of vascular behavior was relatively beneficial to that goal. That’s what
I’d like to explore here. This is the part of the proposed model that is slightly
more speculative, but I think there exist several good clues to support what I
will propose.
I want to begin by reiterating the nature of phospholipids
in the human body. They play an extremely important role in all cellular structure
and function by serving as the structural components of your cell membranes - The
phospholipid bilayer is instrumental in helping regulate membrane fluidity, transport
in and out of the cell, etc. My contention is that the manner by which new phospholipids
reach (and form) the cells of the body plays a very important role in the evolutionary
story of atherosclerosis.
Phospholipid fatty acid tails are hydrophobic (“water-fearing”),
which means they do not travel freely in blood. This is the reason they exist in
the cell membrane as a bilayer, with two hydrophobic tails inward at one
another. So how do they travel in the blood? Well…as lipoproteins, with a large
circle of outward facing phosphate heads and all hydrophobic tails pointed
towards the “safe” interior. For all the emphasis placed on the lipoprotein system
as a carrier of triglycerides and cholesterol, I think a largely ignored but
equally important role is as a carrier of the very phospholipids that make up
their outer shell. While literature focuses on the endocytosis (again, “taking
in”) of lipoproteins into various cells as a manner of delivering cholesterol, it
is by the same logic that this endocytosis may be partially occurring as a
means of delivering new phospholipids for cell membrane synthesis or repair.
This is how phospholipids should be traveling to necessary cellular sites,
because this is how phospholipids exist in the bloodstream.
However, its hard to find definitive studies that seek
to examine this effect. I’d love to see a large study that introduces massive muscular
stress and tracks the corresponding change in LDL-C in response to a
theoretical uptake of LDL particles. More than a year ago, I attempted an experiment
of one to test this very phenomenon. To assess acute changes in LDL-C in response
to muscle damage, I measured morning lipids before running a hilly 50 kilometers
at a pretty reasonable effort. I ate nothing before, during, or immediately
after the run, again measuring lipids about an hour after completing the run.
There were limited changes in LDL-C during the run, increasing only from 106 to
111 mg/dl. I measured lipids a third time the following morning, some 16 hours
after the post-run blood draw (in this time, I ate over 5000 calories of exclusively
fatty animal products such that the day ended up being relatively “calorie-neutral”).
Its worth noting here that the lifespan of an average
LDL particle is in the ballpark of 3-4 days. That is to say, the time between
my post-run and morning-after blood draws represented about one-fifth the lifespan
of an LDL particle. During this time, it would of course be unreasonable to
suggest that my body simply ceased to create new VLDL particles (and perhaps
the diet-heart hypothesis would suggest that my saturated fat binge would even
lead to increased production…), so any meaningful decline in LDL-C would have
to be the product of LDL particle disappearance. This was my hypothesis going in,
and indeed this is what happened – LDL-C came back the next morning at 85mg/dl,
a drop of about 24% in just 16 hours. This, to me, confirmed my suspicion that
LDL particles would be taken up as raw material for cell membrane repair, and
frankly helped solidify my belief in the evolutionary model I’m proposing.
To be clear, I think there is other scientific
evidence to support the notion that LDL particles are taken up for cell
membrane synthesis – namely, children. Children tend to have lower LDL-C levels
than grown adults, but this is especially true in two cases in particular –
infancy, and during puberty.7,239–243
“The LDL-C shows a continuous
decrease from 11 to 14 years of age for boys and from 9 to 13 years of age for
girls. This decrease in LDL-C must be the pubertal change”241
“Throughout puberty,
levels of total cholesterol, low density lipoprotein-cholesterol, and nonhigh
density lipoprotein-cholesterol decreased”240
I’ve always had the impression that infant LDL-C is
explained by the medical community as evidence that babies simply haven’t had time
to poison themselves with meat (this is a semi-sarcastic statement, but only
semi-), but that of course does nothing to explain the consistent drop
associated with puberty. What does explain these two transient periods
of low LDL-C is the growing body. LDL-C bottoming out at the two periods of
greatest growth in the human lifespan is highly consistent with the need to
take up these LDL particles as a source of materials for new cell membrane
synthesis.
So multiple lines of evidence for LDL-C lowering in
instances of phospholipid demand, combined with the physiologic reality of these
primary phospholipid-carrying particles being taken up by cells for other delivery
purposes, strongly suggests that lipoproteins (most significantly, LDL), are
the body’s source of phospholipids for cell membrane construction.
This is extremely important for understanding the why of an adaptation that encourages entrapment of and immune response to damaged LDL particles – because, simply, the damaged phospholipids that comprise that particle are potentially destined for construction of a cell membrane that would then itself be damaged. I don’t think your body “wants” to be building or repairing cells with damaged phospholipids, phospholipids that continue to be susceptible to consequences of free radicals and other oxidative stress after integration into the cell membrane.
This is the evolutionary argument in a nutshell:
- Instances of diet encouraging a less favorable
metabolic and vascular environment would have been far less common and less acutely
detrimental in our ancestral past
- Retained metabolic health and reverse cholesterol transport
function would have rendered transient episodes of immune-mediated LDL particle
entrapment unconcerning
- Phospholipids traveling the bloodstream as
lipoproteins are also the source of cell membrane phospholipids
- The reason the body prefers these initiating
atherosclerotic responses is to prevent damaged and highly susceptible phospholipids
from being incorporated into cell membranes
- It is an evolutionary survival advantage to allow the
body to sequester and clear damaged lipoproteins in blood vessels rather than
allow their phospholipids to contribute to cell membrane dysfunction
- Modern atherosclerosis by and large exists because it
is exceedingly common to chronically and on a daily basis overwhelm these
systems with metabolic impairment, elevated blood sugar, and oxidative stress,
rendering attempts to clear the resultant damage insufficient
2. Dawber TR, Moore FE, Mann GV. II. Coronary Heart Disease in the Framingham Study. Am J Public Health Nations Health. 1957;47(4 Pt 2):4-24.
3. Ai M, Otokozawa S, Asztalos BF, et al. Small Dense LDL Cholesterol and Coronary Heart Disease: Results from the Framingham Offspring Study. Accessed February 26, 2026. https://dx.doi.org/10.1373/clinchem.2009.137489
4. Frantz ID, Dawson EA, Ashman PL, et al. Test of effect of lipid lowering by diet on cardiovascular risk. The Minnesota Coronary Survey. Arterioscler Dallas Tex. 1989;9(1):129-135. doi:10.1161/01.atv.9.1.129
5. Ramsden CE, Zamora D, Majchrzak-Hong S, et al. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73). BMJ. 2016;353:i1246. doi:10.1136/bmj.i1246
6. Borén J, Chapman MJ, Krauss RM, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Accessed February 26, 2026. https://dx.doi.org/10.1093/eurheartj/ehz962
7. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459-2472. doi:10.1093/eurheartj/ehx144
8. Mortensen MB, Nordestgaard BG. Elevated LDL cholesterol and increased risk of myocardial infarction and atherosclerotic cardiovascular disease in individuals aged 70–100 years: a contemporary primary prevention cohort. The Lancet. 2020;396(10263):1644-1652. doi:10.1016/S0140-6736(20)32233-9
9. Gender difference of association between LDL cholesterol concentrations and mortality from coronary heart disease amongst Japanese: the Ibaraki Prefectural Health Study - Noda - 2010 - Journal of Internal Medicine - Wiley Online Library. Accessed August 7, 2022. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2796.2009.02183.x
10. Is Isolated Low High-Density Lipoprotein Cholesterol a Cardiovascular Disease Risk Factor? doi:10.1161/CIRCOUTCOMES.115.002436
11. Luz PL da, Favarato D, Faria-Neto Junior JR, Lemos P, Chagas ACP. High ratio of triglycerides to hdl-cholesterol predicts extensive coronary disease. Clinics. 2008;63:427-432. doi:10.1590/S1807-59322008000400003
12. Ueda P, Gulayin P, Danaei G. Long-term moderately elevated LDL-cholesterol and blood pressure and risk of coronary heart disease. PLOS ONE. 2018;13(7):e0200017. doi:10.1371/journal.pone.0200017
13. Gruppen EG, Riphagen IJ, Connelly MA, Otvos JD, Bakker SJL, Dullaart RPF. GlycA, a Pro-Inflammatory Glycoprotein Biomarker, and Incident Cardiovascular Disease: Relationship with C-Reactive Protein and Renal Function. Shimosawa T, ed. PLOS ONE. 2015;10(9):e0139057. doi:10.1371/journal.pone.0139057
14. Casta ñer O, Pint ó X, Subirana I, et al. Remnant Cholesterol, Not LDL Cholesterol, Is Associated With Incident Cardiovascular Disease. J Am Coll Cardiol. 2020;76(23):2712-2724. doi:10.1016/j.jacc.2020.10.008
15. Hoogeveen RC, Gaubatz JW, Sun W, et al. Small Dense Low-Density Lipoprotein-Cholesterol Concentrations Predict Risk for Coronary Heart Disease. Arterioscler Thromb Vasc Biol. 2014;34(5):1069-1077. doi:10.1161/ATVBAHA.114.303284
16. Silbernagel G, Scharnagl H, Saely CH, et al. The LDL Apolipoprotein B-to-LDL Cholesterol Ratio: Association with Cardiovascular Mortality and a Biomarker of Small, Dense LDLs. Biomedicines. 2022;10(6):1302. doi:10.3390/biomedicines10061302
17. Hong S, Han K, Park CY. The triglyceride glucose index is a simple and low-cost marker associated with atherosclerotic cardiovascular disease: a population-based study. BMC Med. 2020;18:361. doi:10.1186/s12916-020-01824-2
18. Li Y, Li Y, Meng L, Zheng L. Association between Serum C-Peptide as a Risk Factor for Cardiovascular Disease and High-Density Lipoprotein Cholesterol Levels in Nondiabetic Individuals. PLOS ONE. 2015;10(1):e112281. doi:10.1371/journal.pone.0112281
19. Dugani SB, Moorthy MV, Li C, et al. Association of Lipid, Inflammatory, and Metabolic Biomarkers With Age at Onset for Incident Coronary Heart Disease in Women. JAMA Cardiol. 2021;6(4):437-447. doi:10.1001/jamacardio.2020.7073
20. Ravnskov U, Diamond DM, Hama R, et al. Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open. 2016;6(6):e010401. doi:10.1136/bmjopen-2015-010401
21. Lu JM, Wu MY, Yang ZM, et al. Low LDL-C levels are associated with risk of mortality in a Chinese cohort study. Endocrine. 2021;73(3):563-572. doi:10.1007/s12020-021-02746-6
22. Schupf N, Costa R, Luchsinger J, Tang MX, Lee JH, Mayeux R. Relationship Between Plasma Lipids and All-Cause Mortality in Nondemented Elderly. J Am Geriatr Soc. 2005;53(2):219-226. doi:10.1111/j.1532-5415.2005.53106.x
23. Johannesen CDL, Langsted A, Mortensen MB, Nordestgaard BG. Association between low density lipoprotein and all cause and cause specific mortality in Denmark: prospective cohort study. BMJ. 2020;371:m4266. doi:10.1136/bmj.m4266
24. Cabrera MAS, de Andrade SM, Dip RM. Lipids and All-Cause Mortality among Older Adults: A 12-Year Follow-Up Study. Sci World J. 2012;2012:e930139. doi:10.1100/2012/930139
25. Bathum L, Depont Christensen R, Engers Pedersen L, Lyngsie Pedersen P, Larsen J, Nexøe J. Association of lipoprotein levels with mortality in subjects aged 50 + without previous diabetes or cardiovascular disease: A population-based register study. Scand J Prim Health Care. 2013;31(3):172-180. doi:10.3109/02813432.2013.824157
26. Liu Y, Liu F, Zhang L, et al. Association between low density lipoprotein cholesterol and all-cause mortality: results from the NHANES 1999–2014. Sci Rep. 2021;11(1):1. doi:10.1038/s41598-021-01738-w
27. Keller F. bluenote10/ChinaStudyRawData. Published online February 8, 2026. Accessed February 26, 2026. https://github.com/bluenote10/ChinaStudyRawData
28. NHANES - National Health and Nutrition Examination Survey Homepage. December 9, 2022. Accessed December 14, 2022. https://www.cdc.gov/nchs/nhanes/index.htm
29. LDL Receptor - an overview | ScienceDirect Topics. Accessed February 26, 2026. https://www.sciencedirect.com/topics/medicine-and-dentistry/ldl-receptor
30. Kume N, Murase T, Moriwaki H, et al. Inducible Expression of Lectin-like Oxidized LDL Receptor-1 in Vascular Endothelial Cells. Circ Res. 1998;83(3):322-327. doi:10.1161/01.RES.83.3.322
31. Twigg MW, Freestone K, Homer-Vanniasinkam S, Ponnambalam S. The LOX-1 Scavenger Receptor and Its Implications in the Treatment of Vascular Disease. Cardiol Res Pract. 2012;2012:e632408. doi:10.1155/2012/632408
32. Sawamura T, Wakabayashi I, Okamura T. LOX-1 in atherosclerotic disease. Clin Chim Acta. 2015;440:157-163. doi:10.1016/j.cca.2014.11.016
33. Calvo D, Gómez-Coronado D, Suárez Y, Lasunción MA, Vega MA. Human CD36 is a high affinity receptor for the native lipoproteins HDL, LDL, and VLDL. J Lipid Res. 1998;39(4):777-788. doi:10.1016/S0022-2275(20)32566-9
34. Han J, Hajjar DP, Febbraio M, Nicholson AC. Native and Modified Low Density Lipoproteins Increase the Functional Expression of the Macrophage Class B Scavenger Receptor, CD36 *. J Biol Chem. 1997;272(34):21654-21659. doi:10.1074/jbc.272.34.21654
35. Endemann G, Stanton LW, Madden KS, Bryant CM, White RT, Protter AA. CD36 is a receptor for oxidized low density lipoprotein. J Biol Chem. 1993;268(16):11811-11816.
36. Acton SL, Scherer PE, Lodish HF, Krieger M. Expression cloning of SR-BI, a CD36-related class B scavenger receptor. J Biol Chem. 1994;269(33):21003-21009.
37. Gillotte-Taylor K, Boullier A, Witztum JL, Steinberg D, Quehenberger O. Scavenger receptor class B type I as a receptor for oxidized low density lipoprotein. J Lipid Res. 2001;42(9):1474-1482. doi:10.1016/S0022-2275(20)30281-9
38. Armstrong SM, Sugiyama MG, Fung KYY, et al. A novel assay uncovers an unexpected role for SR-BI in LDL transcytosis. Accessed February 26, 2026. https://dx.doi.org/10.1093/cvr/cvv218
39. Jono T, Miyazaki A, Nagai R, Sawamura T, Kitamura T, Horiuchi S. Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) serves as an endothelial receptor for advanced glycation end products (AGE). FEBS Lett. 2002;511(1):170-174. doi:10.1016/S0014-5793(01)03325-7
40. Deshmane SL, Kremlev S, Amini S, Sawaya BE. Monocyte Chemoattractant Protein-1 (MCP-1): An Overview. J Interferon Cytokine Res. 2009;29(6):313-326. doi:10.1089/jir.2008.0027
41. Linton MF, Yancey PG, Davies SS, et al. The Role of Lipids and Lipoproteins in Atherosclerosis. In: Feingold KR, Anawalt B, Boyce A, et al., eds. Endotext. MDText.com, Inc.; 2000. Accessed August 17, 2022. http://www.ncbi.nlm.nih.gov/books/NBK343489/
42. Ley K, Huo Y. VCAM-1 is critical in atherosclerosis. J Clin Invest. 2001;107(10):1209-1210. doi:10.1172/JCI13005
43. Shu HB, Agranoff AB, Nabel EG, et al. Differential regulation of vascular cell adhesion molecule 1 gene expression by specific NF-kappa B subunits in endothelial and epithelial cells. Mol Cell Biol. 1993;13(10):6283-6289. doi:10.1128/mcb.13.10.6283-6289.1993
44. ICAM-1 and VCAM-1: Gatekeepers in various inflammatory and cardiovascular disorders. Clin Chim Acta. 2023;548:117487. doi:10.1016/j.cca.2023.117487
45. Gerszten RE, Garcia-Zepeda EA, Lim YC, et al. MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature. 1999;398(6729):718-723. doi:10.1038/19546
46. Landry DB, Couper LL, Bryant SR, Lindner V. Activation of the NF-kappa B and I kappa B system in smooth muscle cells after rat arterial injury. Induction of vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1. Am J Pathol. 1997;151(4):1085-1095.
47. Tsai KL, Chen LH, Chiou SH, et al. Coenzyme Q10 suppresses oxLDL-induced endothelial oxidative injuries by the modulation of LOX-1-mediated ROS generation via the AMPK/PKC/NADPH oxidase signaling pathway. Mol Nutr Food Res. 2011;55(S2):S227-S240. doi:10.1002/mnfr.201100147
48. Lubrano V, Balzan S. LOX-1 and ROS, inseparable factors in the process of endothelial damage. Free Radic Res. 2014;48(8):841-848. doi:10.3109/10715762.2014.929122
49. Naseem KM. The role of nitric oxide in cardiovascular diseases. Mol Aspects Med. 2005;26(1):33-65. doi:10.1016/j.mam.2004.09.003
50. Williams IL, Wheatcroft SB, Shah AM, Kearney MT. Obesity, atherosclerosis and the vascular endothelium: mechanisms of reduced nitric oxide bioavailability in obese humans. Int J Obes. 2002;26(6):6. doi:10.1038/sj.ijo.0801995
51. Oemar BS, Tschudi MR, Godoy N, Brovkovich V, Malinski T, Lüscher TF. Reduced Endothelial Nitric Oxide Synthase Expression and Production in Human Atherosclerosis. Circulation. 1998;97(25):2494-2498. doi:10.1161/01.CIR.97.25.2494
52. Chen J yi, Ye Z xin, Wang X fen, et al. Nitric oxide bioavailability dysfunction involves in atherosclerosis. Biomed Pharmacother. 2018;97:423-428. doi:10.1016/j.biopha.2017.10.122
53. Quagliariello V, Bonelli A, Paccone A, et al. Oxidized Low-Density Lipoproteins increases nivolumab-induced cardiotoxicity through TLR4/NF-KB and NLRP3 pathways. Eur Heart J. 2021;42(Supplement_1):ehab724.2837. doi:10.1093/eurheartj/ehab724.2837
54. Robbesyn F, Salvayre R, Negre-Salvayre A. Dual role of oxidized LDL on the NF-kappaB signaling pathway. Free Radic Res. 2004;38(6):541-551. doi:10.1080/10715760410001665244
55. Galkina E, Ley K. Vascular adhesion molecules in atherosclerosis. Arterioscler Thromb Vasc Biol. 2007;27(11):2292-2301. doi:10.1161/ATVBAHA.107.149179
56. Hernandez GE, Iruela-Arispe ML. The many flavors of monocyte / macrophage-endothelial cell interactions. Curr Opin Hematol. 2020;27(3):181-189. doi:10.1097/MOH.0000000000000573
57. Moore K, Sheedy F, Fisher E. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol. 2013;13(10):709-721. doi:10.1038/nri3520
58. Shiratsuch H, Basson MD. Differential regulation of monocyte/macrophage cytokine production by pressure. Am J Surg. 2005;190(5):757-762. doi:10.1016/j.amjsurg.2005.07.016
59. Fadok V, McDonald P, Bratton D, Henson P. Regulation of macrophage cytokine production by phagocytosis of apoptotic and post-apoptotic cells. Biochem Soc Trans. 1998;26:653-656. doi:10.1042/bst0260653
60. Fibrous cap formation or destruction — the critical importance of vascular smooth muscle cell proliferation, migration and matrix formation | Cardiovascular Research | Oxford Academic. Accessed August 17, 2022. https://academic.oup.com/cardiovascres/article/41/2/345/306741
61. Niu C, Wang X, Zhao M, et al. Macrophage Foam Cell–Derived Extracellular Vesicles Promote Vascular Smooth Muscle Cell Migration and Adhesion. J Am Heart Assoc. 5(10):e004099. doi:10.1161/JAHA.116.004099
62. Boyle JJ. Macrophage Activation in Atherosclerosis: Pathogenesis and Pharmacology of Plaque Rupture. Curr Vasc Pharmacol. 2005;3(1):63-68. doi:10.2174/1570161052773861
63. Plihtari R, Kovanen PT, Öörni K. Acidity increases the uptake of native LDL by human monocyte-derived macrophages. Atherosclerosis. 2011;217(2):401-406. doi:10.1016/j.atherosclerosis.2011.04.013
64. Gleissner CA, Leitinger N, Ley K. Effects of Native and Modified Low-Density Lipoproteins on Monocyte Recruitment in Atherosclerosis. Hypertension. 2007;50(2):276-283. doi:10.1161/HYPERTENSIONAHA.107.089854
65. Berliner JA, Territo MC, Sevanian A, et al. Minimally modified low density lipoprotein stimulates monocyte endothelial interactions. J Clin Invest. 1990;85(4):1260-1266. doi:10.1172/JCI114562
66. Zwaka TP, Hombach V, Torzewski J. C-Reactive Protein–Mediated Low Density Lipoprotein Uptake by Macrophages. Circulation. 2001;103(9):1194-1197. doi:10.1161/01.CIR.103.9.1194
67. Keidar S, Kaplan M, Aviram M. Angiotensin II–Modified LDL Is Taken Up by Macrophages Via the Scavenger Receptor, Leading to Cellular Cholesterol Accumulation. Arterioscler Thromb Vasc Biol. 1996;16(1):97-105. doi:10.1161/01.ATV.16.1.97
68. Tanner FC, Noll G, Boulanger CM, Lüscher TF. Oxidized low density lipoproteins inhibit relaxations of porcine coronary arteries. Role of scavenger receptor and endothelium-derived nitric oxide. Circulation. 1991;83(6):2012-2020. doi:10.1161/01.CIR.83.6.2012
69. Murphy AA, Palinski W, Rankin S, Morales AJ, Parthasarathy S. Macrophage Scavenger Receptor(s) and Oxidatively Modified Proteins in Endometriosis. Fertil Steril. 1998;69(6):1085-1091. doi:10.1016/S0015-0282(98)00088-0
70. Chait A, Brazg RL, Tribble DL, Krauss RM. Susceptibility of small, dense, low-density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern B. Am J Med. 1993;94(4):350-356. doi:10.1016/0002-9343(93)90144-E
71. Hurt-Camejo E, Camejo G, Rosengren B, et al. Effect of arterial proteoglycans and glycosaminoglycans on low density lipoprotein oxidation and its uptake by human macrophages and arterial smooth muscle cells. Arterioscler Thromb J Vasc Biol. 1992;12(5):569-583. doi:10.1161/01.ATV.12.5.569
72. Soran H, Durrington PN. Susceptibility of LDL and its subfractions to glycation. Curr Opin Lipidol. 2011;22(4):254-261. doi:10.1097/MOL.0b013e328348a43f
73. Younis N, Sharma R, Soran H, Charlton-Menys V, Elseweidy M, Durrington PN. Glycation as an atherogenic modification of LDL. Curr Opin Lipidol. 2008;19(4):378-384. doi:10.1097/MOL.0b013e328306a057
74. Sobal G, Menzel J, Sinzinger H. Why is glycated LDL more sensitive to oxidation than native LDL? A comparative study. Prostaglandins Leukot Essent Fatty Acids. 2000;63(4):177-186. doi:10.1054/plef.2000.0204
75. Toma L, Stancu CS, Botez GM, Sima AV, Simionescu M. Irreversibly glycated LDL induce oxidative and inflammatory state in human endothelial cells; added effect of high glucose. Biochem Biophys Res Commun. 2009;390(3):877-882. doi:10.1016/j.bbrc.2009.10.066
76. Veiraiah A. Hyperglycemia, Lipoprotein Glycation, and Vascular Disease. Angiology. 2005;56(4):431-438. doi:10.1177/000331970505600411
77. Al Saudi RM, Kasabri V, Naffa R, Bulatova N, Bustanji Y. Glycated LDL-C and glycated HDL-C in association with adiposity, blood and atherogenicity indices in metabolic syndrome patients with and without prediabetes. Ther Adv Endocrinol Metab. 2018;9(10):311-323. doi:10.1177/2042018818788198
78. Hudson BI, Dong C, Gardener H, et al. Serum levels of soluble receptor for advanced glycation end-products and metabolic syndrome: The Northern Manhattan Study. Metabolism. 2014;63(9):1125-1130. doi:10.1016/j.metabol.2014.05.011
79. Uribarri J, Cai W, Woodward M, et al. Elevated Serum Advanced Glycation Endproducts in Obese Indicate Risk for the Metabolic Syndrome: A Link Between Healthy and Unhealthy Obesity? J Clin Endocrinol Metab. 2015;100(5):1957-1966. doi:10.1210/jc.2014-3925
80. Softic S, Cohen DE, Kahn CR. Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease. Dig Dis Sci. 2016;61(5):1282-1293. doi:10.1007/s10620-016-4054-0
81. Marques-Lopes I, Ansorena D, Astiasaran I, Forga L, Martínez JA. Postprandial de novo lipogenesis and metabolic changes induced by a high-carbohydrate, low-fat meal in lean and overweight men. Am J Clin Nutr. 2001;73(2):253-261. doi:10.1093/ajcn/73.2.253
82. Schwarz JM, Linfoot P, Dare D, Aghajanian K. Hepatic de novo lipogenesis in normoinsulinemic and hyperinsulinemic subjects consuming high-fat, low-carbohydrate and low-fat, high-carbohydrate isoenergetic diets. Am J Clin Nutr. 2003;77(1):43-50. doi:10.1093/ajcn/77.1.43
83. Forsythe CE, Phinney SD, Feinman RD, et al. Limited Effect of Dietary Saturated Fat on Plasma Saturated Fat in the Context of a Low Carbohydrate Diet. Lipids. 2010;45(10):947-962. doi:10.1007/s11745-010-3467-3
84. Volek JS, Sharman MJ, Gómez AL, Scheett TP, Kraemer WJ. An Isoenergetic Very Low Carbohydrate Diet Improves Serum HDL Cholesterol and Triacylglycerol Concentrations, the Total Cholesterol to HDL Cholesterol Ratio and Postprandial Lipemic Responses Compared with a Low Fat Diet in Normal Weight, Normolipidemic Women. J Nutr. 2003;133(9):2756-2761. doi:10.1093/jn/133.9.2756
85. Mousavi SM, Ejtahed HS, Marvasti FE, et al. The Effect of a Moderately Restricted Carbohydrate Diet on Cardiometabolic Risk Factors in Overweight and Obese Women With Metabolic Syndrome: A Randomized Controlled Trial. Clin Ther. Published online March 4, 2023. doi:10.1016/j.clinthera.2023.02.002
86. Foster GD, Wyatt HR, Hill JO, et al. A Randomized Trial of a Low-Carbohydrate Diet for Obesity. N Engl J Med. 2003;348(21):2082-2090. doi:10.1056/NEJMoa022207
87. Yamada Y, Uchida J, Izumi H, et al. A Non-calorie-restricted Low-carbohydrate Diet is Effective as an Alternative Therapy for Patients with Type 2 Diabetes. Intern Med. 2014;53(1):13-19. doi:10.2169/internalmedicine.53.0861
88. Parks EJ, Krauss RM, Christiansen MP, Neese RA, Hellerstein MK. Effects of a low-fat, high-carbohydrate diet on VLDL-triglyceride assembly, production, and clearance. J Clin Invest. 1999;104(8):1087-1096. doi:10.1172/JCI6572
89. Chiu S, Bergeron N, Williams PT, Bray GA, Sutherland B, Krauss RM. Comparison of the DASH (Dietary Approaches to Stop Hypertension) diet and a higher-fat DASH diet on blood pressure and lipids and lipoproteins: a randomized controlled trial1–3. Am J Clin Nutr. 2016;103(2):341-347. doi:10.3945/ajcn.115.123281
90. Properzi C, O’Sullivan TA, Sherriff JL, et al. Ad Libitum Mediterranean and Low-Fat Diets Both Significantly Reduce Hepatic Steatosis: A Randomized Controlled Trial. Hepatology. 2018;68(5):1741-1754. doi:10.1002/hep.30076
91. Bradley U, Spence M, Courtney CH, et al. Low-Fat Versus Low-Carbohydrate Weight Reduction Diets: Effects on Weight Loss, Insulin Resistance, and Cardiovascular Risk: A Randomized Control Trial. Diabetes. 2009;58(12):2741-2748. doi:10.2337/db09-0098
92. Marckmann P, Sandström B, Jespersen J. Low-fat, high-fiber diet favorably affects several independent risk markers of ischemic heart disease: observations on blood lipids, coagulation, and fibrinolysis from a trial of middle-aged Danes. Am J Clin Nutr. 1994;59(4):935-939. doi:10.1093/ajcn/59.4.935
93. Bazzano LA, Hu T, Reynolds K, et al. Effects of Low-Carbohydrate and Low-Fat Diets. Ann Intern Med. 2014;161(5):309-318. doi:10.7326/M14-0180
94. Ebbeling CB, Leidig MM, Feldman HA, Lovesky MM, Ludwig DS. Effects of a Low–Glycemic Load vs Low-Fat Diet in Obese Young AdultsA Randomized Trial. JAMA. 2007;297(19):2092-2102. doi:10.1001/jama.297.19.2092
95. Dashti HM, Mathew TC, Hussein T, et al. Long-term effects of a ketogenic diet in obese patients. Exp Clin Cardiol. 2004;9(3):200-205.
96. Dashti H, Bo-Abbas Y, Asfar S, et al. Ketogenic diet modifies the risk factors of heart disease in obese patients. Nutr Burbank Los Angel Cty Calif. 2003;19:901-902. doi:10.1016/S0899-9007(03)00161-8
97. Dashti HM, Mathew TC, Khadada M, et al. Beneficial effects of ketogenic diet in obese diabetic subjects. Mol Cell Biochem. 2007;302(1):249-256. doi:10.1007/s11010-007-9448-z
98. Abbasi F, McLaughlin T, Lamendola C, et al. High carbohydrate diets, triglyceride-rich lipoproteins, and coronary heart disease risk. Am J Cardiol. 2000;85(1):45-48. doi:10.1016/S0002-9149(99)00604-9
99. Shai I, Schwarzfuchs D, Henkin Y, et al. Weight Loss with a Low-Carbohydrate, Mediterranean, or Low-Fat Diet. N Engl J Med. 2008;359(3):229-241. doi:10.1056/NEJMoa0708681
100. Brinkworth GD, Noakes M, Buckley JD, Keogh JB, Clifton PM. Long-term effects of a very-low-carbohydrate weight loss diet compared with an isocaloric low-fat diet after 12 mo. Am J Clin Nutr. 2009;90(1):23-32. doi:10.3945/ajcn.2008.27326
101. Hudgins LC, Hellerstein M, Seidman C, Neese R, Diakun J, Hirsch J. Human fatty acid synthesis is stimulated by a eucaloric low fat, high carbohydrate diet. J Clin Invest. 1996;97(9):2081-2091. doi:10.1172/JCI118645
102. Nordmann AJ, Nordmann A, Briel M, et al. Effects of Low-Carbohydrate vs Low-Fat Diets on Weight Loss and Cardiovascular Risk Factors: A Meta-analysis of Randomized Controlled Trials. Arch Intern Med. 2006;166(3):285-293. doi:10.1001/archinte.166.3.285
103. Ruth MR, Port AM, Shah M, et al. Consuming a hypocaloric high fat low carbohydrate diet for 12weeks lowers C-reactive protein, and raises serum adiponectin and high density lipoprotein-cholesterol in obese subjects. Metabolism. 2013;62(12):1779-1787. doi:10.1016/j.metabol.2013.07.006
104. Parillo M, Rivellese AA, Ciardullo AV, et al. A high-monounsaturated-fat/low-carbohydrate diet improves peripheral insulin sensitivity in non-insulin-dependent diabetic patients. Metabolism. 1992;41(12):1373-1378. doi:10.1016/0026-0495(92)90111-M
105. Huntriss R, Campbell M, Bedwell C. The interpretation and effect of a low-carbohydrate diet in the management of type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials. Eur J Clin Nutr. 2018;72(3):3. doi:10.1038/s41430-017-0019-4
106. Martens EA, Gatta-Cherifi B, Gonnissen HK, Westerterp-Plantenga MS. The Potential of a High Protein-Low Carbohydrate Diet to Preserve Intrahepatic Triglyceride Content in Healthy Humans. PLOS ONE. 2014;9(10):e109617. doi:10.1371/journal.pone.0109617
107. Sanfelippo ML, Swenson RS, Reaven GM. Reduction of plasma triglycerides by diet in subjects with chronic renal failure. Kidney Int. 1977;11(1):54-61. doi:10.1038/ki.1977.7
108. Stern L, Iqbal N, Seshadri P, et al. The Effects of Low-Carbohydrate versus Conventional Weight Loss Diets in Severely Obese Adults: One-Year Follow-up of a Randomized Trial. Ann Intern Med. 2004;140(10):778-785. doi:10.7326/0003-4819-140-10-200405180-00007
109. Volek JS, Sharman MJ. Cardiovascular and Hormonal Aspects of Very-Low-Carbohydrate Ketogenic Diets. Obes Res. 2004;12(S11):115S-123S. doi:10.1038/oby.2004.276
110. Hays JH, DiSabatino A, Gorman RT, Vincent S, Stillabower ME. Effect of a high saturated fat and no-starch diet on serum lipid subfractions in patients with documented atherosclerotic cardiovascular disease. Mayo Clin Proc. 2003;78(11):1331-1336. doi:10.4065/78.11.1331
111. Kirkpatrick CF, Bolick JP, Kris-Etherton PM, et al. Review of current evidence and clinical recommendations on the effects of low-carbohydrate and very-low-carbohydrate (including ketogenic) diets for the management of body weight and other cardiometabolic risk factors: A scientific statement from the National Lipid Association Nutrition and Lifestyle Task Force. J Clin Lipidol. 2019;13(5):689-711.e1. doi:10.1016/j.jacl.2019.08.003
112. Schwingshackl L, Hoffmann G. Comparison of Effects of Long-Term Low-Fat vs High-Fat Diets on Blood Lipid Levels in Overweight or Obese Patients: A Systematic Review and Meta-Analysis. J Acad Nutr Diet. 2013;113(12):1640-1661. doi:10.1016/j.jand.2013.07.010
113. Chawla S, Tessarolo Silva F, Amaral Medeiros S, Mekary RA, Radenkovic D. The Effect of Low-Fat and Low-Carbohydrate Diets on Weight Loss and Lipid Levels: A Systematic Review and Meta-Analysis. Nutrients. 2020;12(12):12. doi:10.3390/nu12123774
114. Yancy WS, Olsen MK, Guyton JR, Bakst RP, Westman EC. A Low-Carbohydrate, Ketogenic Diet versus a Low-Fat Diet To Treat Obesity and Hyperlipidemia. Ann Intern Med. 2004;140(10):769-777. doi:10.7326/0003-4819-140-10-200405180-00006
115. Guay V, Lamarche B, Charest A, Tremblay AJ, Couture P. Effect of short-term low- and high-fat diets on low-density lipoprotein particle size in normolipidemic subjects. Metabolism. 2012;61(1):76-83. doi:10.1016/j.metabol.2011.06.002
116. Sharman MJ, Kraemer WJ, Love DM, et al. A Ketogenic Diet Favorably Affects Serum Biomarkers for Cardiovascular Disease in Normal-Weight Men. J Nutr. 2002;132(7):1879-1885. doi:10.1093/jn/132.7.1879
117. Samaha FF, Iqbal N, Seshadri P, et al. A Low-Carbohydrate as Compared with a Low-Fat Diet in Severe Obesity. N Engl J Med. 2003;348(21):2074-2081. doi:10.1056/NEJMoa022637
118. Harvey CJ d C, Schofield GM, Zinn C, Thornley SJ, Crofts C, Merien FLR. Low-carbohydrate diets differing in carbohydrate restriction improve cardiometabolic and anthropometric markers in healthy adults: A randomised clinical trial. PeerJ. 2019;7:e6273. doi:10.7717/peerj.6273
119. Wolfe BMJ, Piche LA. Replacement of carbohydrate by protein in conventional-fat diet reduces cholesterol and triglyceride concentrations in healthy normolipidemic subjects. Clin Invest Med. 1999;22(4):140-148.
120. Gan CF, Gong RR, Lin J, et al. [Effects of high-carbohydrate/low-fat diet on serum lipid ratios in healthy young subjects]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2008;39(2):267-271, 275.
121. Meng Y, Bai H, Wang S, Li Z, Wang Q, Chen L. Efficacy of low carbohydrate diet for type 2 diabetes mellitus management: A systematic review and meta-analysis of randomized controlled trials. Diabetes Res Clin Pract. 2017;131:124-131. doi:10.1016/j.diabres.2017.07.006
122. Mutungi G, Ratliff J, Puglisi M, et al. Dietary Cholesterol from Eggs Increases Plasma HDL Cholesterol in Overweight Men Consuming a Carbohydrate-Restricted Diet. J Nutr. 2008;138(2):272-276. doi:10.1093/jn/138.2.272
123. MEYER N, DIEKMANN LM, KABISCH S, DAMBECK U, PFEIFFER AF. 784-P: Effects of Low-Carb and Low-Fat Dietary Strategies on Lipid Profile in Subjects with Prediabetes—DiNA-P. Diabetes. 2019;68(Supplement_1):784-P. doi:10.2337/db19-784-P
124. Asztalos B, Lefevre M, Wong L, et al. Differential response to low-fat diet between low and normal HDL-cholesterol subjects. J Lipid Res. 2000;41(3):321-328. doi:10.1016/S0022-2275(20)34470-9
125. Vélez-Carrasco W, Lichtenstein AH, Welty FK, et al. Dietary Restriction of Saturated Fat and Cholesterol Decreases HDL ApoA-I Secretion. Arterioscler Thromb Vasc Biol. 1999;19(4):918-924. doi:10.1161/01.ATV.19.4.918
126. DELTA Investigators. HDL-subpopulation patterns in response to reductions in dietary total and saturated fat intakes in healthy subjects. Am J Clin Nutr. 1999;70(6):992-1000. doi:10.1093/ajcn/70.6.992
127. Siri-Tarino PW, Sun Q, Hu FB, Krauss RM. Saturated fat, carbohydrate, and cardiovascular disease. Am J Clin Nutr. 2010;91(3):502-509. doi:10.3945/ajcn.2008.26285
128. Ehnholm C, Huttunen JK, Pietinen P, et al. Effect of a diet low in saturated fatty acids on plasma lipids, lipoproteins, and HDL subfractions. Arterioscler Off J Am Heart Assoc Inc. 1984;4(3):265-269. doi:10.1161/01.ATV.4.3.265
129. Jackson RL, Yates MT, McNerney CA, Kashyap ML. Diet and HDL Metabolism: High Carbohydrate vs. High Fat Diets. In: Malmendier CL, Alaupovic P, eds. Lipoproteins and Atherosclerosis. Advances in Experimental Medicine and Biology. Springer US; 1987:165-172. doi:10.1007/978-1-4684-1268-0_24
130. Wood RJ, Volek JS, Liu Y, Shachter NS, Contois JH, Fernandez ML. Carbohydrate Restriction Alters Lipoprotein Metabolism by Modifying VLDL, LDL, and HDL Subfraction Distribution and Size in Overweight Men. J Nutr. 2006;136(2):384-389. doi:10.1093/jn/136.2.384
131. Andersen CJ, Blesso CN, Park Y, et al. Carbohydrate restriction favorably affects HDL metabolism in men and women with Metabolic Syndrome. Addition of egg yolk further increases large HDL particles. FASEB J. 2012;26(S1):254.5-254.5. doi:10.1096/fasebj.26.1_supplement.254.5
132. Morgan SA, O’dea K, Sinclair AJ. A Low-Fat Diet Supplemented With Monounsaturated Fat Results in Less HDL-C Lowering Than a Very-Low-Fat Diet. J Am Diet Assoc. 1997;97(2):151-156. doi:10.1016/S0002-8223(97)00770-0
133. Wu L, Ma D, Walton-Moss B, He Z. Effects of low-fat diet on serum lipids in premenopausal and postmenopausal women: a meta-analysis of randomized controlled trials. Menopause. 2014;21(1):89-99. doi:10.1097/GME.0b013e318291f5c2
134. Seim HC, Holtmeier KB. Effects of a six-week, low-fat diet on serum cholesterol, body weight, and body measurements. Fam Pract Res J. 1992;12(4):411-419.
135. Brinton EA, Eisenberg S, Breslow JL. A low-fat diet decreases high density lipoprotein (HDL) cholesterol levels by decreasing HDL apolipoprotein transport rates. J Clin Invest. 1990;85(1):144-151. doi:10.1172/JCI114405
136. Buga A, Welton GL, Scott KE, et al. The Effects of Carbohydrate versus Fat Restriction on Lipid Profiles in Highly Trained, Recreational Distance Runners: A Randomized, Cross-Over Trial. Nutrients. 2022;14(6):6. doi:10.3390/nu14061135
137. Tay J, Thompson CH, Luscombe-Marsh ND, et al. Effects of an energy-restricted low-carbohydrate, high unsaturated fat/low saturated fat diet versus a high-carbohydrate, low-fat diet in type 2 diabetes: A 2-year randomized clinical trial. Diabetes Obes Metab. 2018;20(4):858-871. doi:10.1111/dom.13164
138. Li S, Ding L, Xiao X. Comparing the Efficacy and Safety of Low-Carbohydrate Diets with Low-Fat Diets for Type 2 Diabetes Mellitus Patients: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Int J Endocrinol. 2021;2021:e8521756. doi:10.1155/2021/8521756
139. Freedland SJ, Howard LE, Ngo A, et al. Low Carbohydrate Diets and Estimated Cardiovascular and Metabolic Syndrome Risk in Prostate Cancer. J Urol. 2021;206(6):1411-1419. doi:10.1097/JU.0000000000002112
140. Garg A, Grundy SM, Unger RH. Comparison of Effects of High and Low Carbohydrate Diets on Plasma Lipoproteins and Insulin Sensitivity in Patients With Mild NIDDM. Diabetes. 1992;41(10):1278-1285. doi:10.2337/diab.41.10.1278
141. Koutsari C, Karpe F, Humphreys SM, Frayn KN, Hardman AE. Exercise Prevents the Accumulation of Triglyceride-Rich Lipoproteins and Their Remnants Seen When Changing to a High-Carbohydrate Diet. Arterioscler Thromb Vasc Biol. 2001;21(9):1520-1525. doi:10.1161/hq0901.095553
142. Liu Y, Bharmal SH, Kimita W, Petrov MS. Effect of acute ketosis on lipid profile in prediabetes: findings from a cross-over randomized controlled trial. Cardiovasc Diabetol. 2022;21(1):138. doi:10.1186/s12933-022-01571-z
143. Falkenhain K, Roach LA, McCreary S, et al. Effect of carbohydrate-restricted dietary interventions on LDL particle size and number in adults in the context of weight loss or weight maintenance: a systematic review and meta-analysis. Am J Clin Nutr. 2021;114(4):1455-1466. doi:10.1093/ajcn/nqab212
144. Maruyama C, Imamura K, Teramoto T. Assessment of LDL particle size by triglyceride/HDL-cholesterol ratio in non-diabetic, healthy subjects without prominent hyperlipidemia. J Atheroscler Thromb. 2003;10(3):186-191. doi:10.5551/jat.10.186
145. Julius U, Dittrich M, Pietzsch J. Factors influencing the formation of small dense low-density lipoprotein particles in dependence on the presence of the metabolic syndrome and on the degree of glucose intolerance. Int J Clin Pract. 2007;61(11):1798-1804. doi:10.1111/j.1742-1241.2007.01507.x
146. Westman EC, Yancy WS, Olsen MK, Dudley T, Guyton JR. Effect of a low-carbohydrate, ketogenic diet program compared to a low-fat diet on fasting lipoprotein subclasses. Int J Cardiol. 2006;110(2):212-216. doi:10.1016/j.ijcard.2005.08.034
147. McNamara JR, Jenner JL, Li Z, Wilson PW, Schaefer EJ. Change in LDL particle size is associated with change in plasma triglyceride concentration. Arterioscler Thromb J Vasc Biol. 1992;12(11):1284-1290. doi:10.1161/01.ATV.12.11.1284
148. Stan S, Levy E, Delvin EE, et al. Distribution of LDL Particle Size in a Population-Based Sample of Children and Adolescents and Relationship with Other Cardiovascular Risk Factors. Clin Chem. 2005;51(7):1192-1200. doi:10.1373/clinchem.2004.046771
149. Dreon DM, Fernstrom HA, Williams PT, Krauss RM. Reduced LDL particle size in children consuming a very-low-fat diet is related to parental LDL-subclass patterns. Am J Clin Nutr. 2000;71(6):1611-1616. doi:10.1093/ajcn/71.6.1611
150. Wang L, Tao L, Hao L, et al. A Moderate-Fat Diet with One Avocado per Day Increases Plasma Antioxidants and Decreases the Oxidation of Small, Dense LDL in Adults with Overweight and Obesity: A Randomized Controlled Trial. J Nutr. 2020;150(2):276-284. doi:10.1093/jn/nxz231
151. Fitó M, Guxens M, Corella D, et al. Effect of a traditional Mediterranean diet on lipoprotein oxidation: a randomized controlled trial. Arch Intern Med. 2007;167(11):1195-1203. doi:10.1001/archinte.167.11.1195
152. Vos MB, Weber MB, Welsh J, et al. Fructose and Oxidized LDL in Pediatric Nonalcoholic Fatty Liver Disease: A Pilot Study. Arch Pediatr Adolesc Med. 2009;163(7):674-675. doi:10.1001/archpediatrics.2009.93
153. Jones JL, Comperatore M, Barona J, et al. A Mediterranean-style, low–glycemic-load diet decreases atherogenic lipoproteins and reduces lipoprotein (a) and oxidized low-density lipoprotein in women with metabolic syndrome. Metab - Clin Exp. 2012;61(3):366-372. doi:10.1016/j.metabol.2011.07.013
154. Barona J, Jones JJ, Kopec RE, et al. A Mediterranean-style low-glycemic-load diet increases plasma carotenoids and decreases LDL oxidation in women with metabolic syndrome. J Nutr Biochem. 2012;23(6):609-615. doi:10.1016/j.jnutbio.2011.02.016
155. Silaste ML, Rantala M, Alfthan G, et al. Changes in dietary fat intake alter plasma levels of oxidized low-density lipoprotein and lipoprotein(a). Arterioscler Thromb Vasc Biol. 2004;24(3):498-503. doi:10.1161/01.ATV.0000118012.64932.f4
156. Tanaka J, Qiang L, Banks AS, et al. Foxo1 Links Hyperglycemia to LDL Oxidation and Endothelial Nitric Oxide Synthase Dysfunction in Vascular Endothelial Cells. Diabetes. 2009;58(10):2344-2354. doi:10.2337/db09-0167
157. Di Marco E, Gray S, Jandeleit-Dahm K. Diabetes Alters Activation and Repression of Pro- and Anti-Inflammatory Signaling Pathways in the Vasculature. Front Endocrinol. 2013;4. Accessed October 12, 2022. https://www.frontiersin.org/articles/10.3389/fendo.2013.00068
158. Stirban A, Gawlowski T, Roden M. Vascular effects of advanced glycation endproducts: Clinical effects and molecular mechanisms. Mol Metab. 2014;3(2):94-108. doi:10.1016/j.molmet.2013.11.006
159. Schmidt AM, Hasu M, Popov D, et al. Receptor for advanced glycation end products (AGEs) has a central role in vessel wall interactions and gene activation in response to circulating AGE proteins. Proc Natl Acad Sci U S A. 1994;91(19):8807-8811. doi:10.1073/pnas.91.19.8807
160. C. Tobon-Velasco J, Cuevas E, A. Torres-Ramos M. Receptor for AGEs (RAGE) as Mediator of NF-kB Pathway Activation in Neuroinflammation and Oxidative Stress. CNS Neurol Disord - Drug Targets- CNS Neurol Disord. 2014;13(9):1615-1626.
161. Prasad A, Bekker P, Tsimikas S. Advanced Glycation End Products and Diabetic Cardiovascular Disease. Cardiol Rev. 2012;20(4):177-183. doi:10.1097/CRD.0b013e318244e57c
162. Susic D, Varagic J, Ahn J, Frohlich ED. Collagen Cross-link Breakers:A Beginning of a New Era in the Treatment of Cardiovascular Changes Associated with Aging,Diabetes,and Hypertension. Curr Drug Targets - Cardiovasc Hematol Disord. 2004;4(1):97-101. doi:10.2174/1568006043481347
163. Aronson D. Cross-linking of glycated collagen in the pathogenesis of arterial and myocardial stiffening of aging and diabetes. J Hypertens. 2003;21(1):3-12.
164. Zieman SJ, Kass DA. Advanced Glycation End Product Cross-Linking: Pathophysiologic Role and Therapeutic Target in Cardiovascular Disease. Congest Heart Fail. 2004;10(3):144-151. doi:10.1111/j.1527-5299.2004.03223.x
165. Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced Glycation End Products. Circulation. 2006;114(6):597-605. doi:10.1161/CIRCULATIONAHA.106.621854
166. Iwashima Y, Eto M, Hata A, et al. Advanced glycation end products-induced gene expression of scavenger receptors in cultured human monocyte-derived macrophages. Biochem Biophys Res Commun. 2000;277(2):368-380. doi:10.1006/bbrc.2000.3685
167. Li L, Sawamura T, Renier G. Glucose Enhances Endothelial LOX-1 Expression: Role for LOX-1 in Glucose-Induced Human Monocyte Adhesion to Endothelium. Diabetes. 2003;52(7):1843-1850. doi:10.2337/diabetes.52.7.1843
168. Li L, Sawamura T, Renier G. Glucose Enhances Human Macrophage LOX-1 Expression. Circ Res. 2004;94(7):892-901. doi:10.1161/01.RES.0000124920.09738.26
169. Uchida K, Suehiro A, Nakanishi M, Sawamura T, Wakabayashi I. Associations of atherosclerotic risk factors with oxidized low-density lipoprotein evaluated by LOX-1 ligand activity in healthy men. Clin Chim Acta. 2011;412(17):1643-1647. doi:10.1016/j.cca.2011.05.022
170. Shiu SW, Wong Y, Tan KC. Effect of Advanced Glycation End Products on Lectin-Like Oxidized Low Density Lipoprotein Receptor-1 Expression in Endothelial Cells. J Atheroscler Thromb. 2012;advpub:11742. doi:10.5551/jat.11742
171. Chen X, Zhang T, Du G. Advanced glycation end products serve as ligands for lectin-like oxidized low-density lipoprotein receptor-1(LOX-1): biochemical and binding characterizations assay. Cell Biochem Funct. 2008;26(7):760-770. doi:10.1002/cbf.1502
172. Bucala R, Makita Z, Vega G, et al. Modification of low density lipoprotein by advanced glycation end products contributes to the dyslipidemia of diabetes and renal insufficiency. Proc Natl Acad Sci. 1994;91(20):9441-9445. doi:10.1073/pnas.91.20.9441
173. Vlassara H. Advanced Glycation End-products and Atherosclerosis. Ann Med. 1996;28(5):419-426. doi:10.3109/07853899608999102
174. Griffin E, Re A, Hamel N, et al. A link between diabetes and atherosclerosis: Glucose regulates expression of CD36 at the level of translation. Nat Med. 2001;7(7):840-846. doi:10.1038/89969
175. Farhangkhoee H, Khan ZA, Barbin Y, Chakrabarti S. Glucose-induced up-regulation of CD36 mediates oxidative stress and microvascular endothelial cell dysfunction. Diabetologia. 2005;48(7):1401-1410. doi:10.1007/s00125-005-1801-8
176. Chen M, Yang YK, Loux TJ, Georgeson KE, Harmon CM. The role of hyperglycemia in FAT/CD36 expression and function. Pediatr Surg Int. 2006;22(8):647-654. doi:10.1007/s00383-006-1704-x
177. Lopez-Carmona MD, Plaza-Seron MC, Vargas-Candela A, Tinahones FJ, Gomez-Huelgas R, Bernal-Lopez MR. CD36 overexpression: a possible etiopathogenic mechanism of atherosclerosis in patients with prediabetes and diabetes. Diabetol Metab Syndr. 2017;9(1):55. doi:10.1186/s13098-017-0253-x
178. Sun Y, Scavini M, Orlando RA, et al. Increased CD36 Expression Signals Monocyte Activation Among Patients With Type 2 Diabetes. Diabetes Care. 2010;33(9):2065-2067. doi:10.2337/dc10-0460
179. Steneberg P, Sykaras AG, Backlund F, Straseviciene J, Söderström I, Edlund H. Hyperinsulinemia Enhances Hepatic Expression of the Fatty Acid Transporter Cd36 and Provokes Hepatosteatosis and Hepatic Insulin Resistance*. J Biol Chem. 2015;290(31):19034-19043. doi:10.1074/jbc.M115.640292
180. Sreedevi NN, Mattaparthi R, Saibaba K, et al. Assessment of sCD36 levels and Lipids in Type II Diabetes Mellitus. IOSR J Dent Med Sci. 2018;17:6-10. doi:10.9790/0853-1707030610
181. Kanoke A, Nishijima Y, Ljungberg M, et al. The effect of type 2 diabetes on CD36 expression and the uptake of oxLDL: Diabetes affects CD36 and oxLDL uptake. Exp Neurol. 2020;334:113461. doi:10.1016/j.expneurol.2020.113461
182. Prasad K, Dhar I. Oxidative stress as a mechanism of added sugar-induced cardiovascular disease. Int J Angiol Off Publ Int Coll Angiol Inc. 2014;23(4):217-226. doi:10.1055/s-0034-1387169
183. Jansen H, Verhoeven AJM, Sijbrands EJG. Hepatic lipase. J Lipid Res. 2002;43(9):1352-1362. doi:10.1194/jlr.R200008-JLR200
184. Balteau M, Tajeddine N, de Meester C, et al. NADPH oxidase activation by hyperglycaemia in cardiomyocytes is independent of glucose metabolism but requires SGLT1. Cardiovasc Res. 2011;92:237-246. doi:10.1093/cvr/cvr230
185. Lee Y, Fluckey JD, Chakraborty S, Muthuchamy M. Hyperglycemia- and hyperinsulinemia-induced insulin resistance causes alterations in cellular bioenergetics and activation of inflammatory signaling in lymphatic muscle. FASEB J. 2017;31(7):2744-2759. doi:10.1096/fj.201600887R
186. Stefano GB, Challenger S, Kream RM. Hyperglycemia-associated alterations in cellular signaling and dysregulated mitochondrial bioenergetics in human metabolic disorders. Eur J Nutr. 2016;55(8):2339-2345. doi:10.1007/s00394-016-1212-2
187. Pahwa R, Jialal I. Hyperglycemia Induces Toll-Like Receptor Activity Through Increased Oxidative Stress. Metab Syndr Relat Disord. 2016;14(5):239-241. doi:10.1089/met.2016.29006.pah
188. Khodami B, Hatami B, Yari Z, et al. Effects of a low free sugar diet on the management of nonalcoholic fatty liver disease: a randomized clinical trial. Eur J Clin Nutr. 2022;76(7):7. doi:10.1038/s41430-022-01081-x
189. Morigi M, Angioletti S, Imberti B, et al. Leukocyte-endothelial interaction is augmented by high glucose concentrations and hyperglycemia in a NF-kB-dependent fashion. J Clin Invest. 1998;101(9):1905-1915. doi:10.1172/JCI656
190. Du XL, Edelstein D, Dimmeler S, Ju Q, Sui C, Brownlee M. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest. 2001;108(9):1341-1348. doi:10.1172/JCI11235
191. Klein AV, Kiat H. The mechanisms underlying fructose-induced hypertension: a review. J Hypertens. 2015;33(5):912-920. doi:10.1097/HJH.0000000000000551
192. Kersten JR, Toller WG, Tessmer JP, Pagel PS, Warltier DC. Hyperglycemia reduces coronary collateral blood flow through a nitric oxide-mediated mechanism. Am J Physiol-Heart Circ Physiol. 2001;281(5):H2097-H2104. doi:10.1152/ajpheart.2001.281.5.H2097
193. Cominacini L, Rigoni A, Pasini AF, et al. The Binding of Oxidized Low Density Lipoprotein (ox-LDL) to ox-LDL Receptor-1 Reduces the Intracellular Concentration of Nitric Oxide in Endothelial Cells through an Increased Production of Superoxide *. J Biol Chem. 2001;276(17):13750-13755. doi:10.1074/jbc.M010612200
194. Nieuwdorp M, van Haeften TW, Gouverneur MCLG, et al. Loss of Endothelial Glycocalyx During Acute Hyperglycemia Coincides With Endothelial Dysfunction and Coagulation Activation In Vivo. Diabetes. 2006;55(2):480-486. doi:10.2337/diabetes.55.02.06.db05-1103
195. Aldecoa C, Llau JV, Nuvials X, Artigas A. Role of albumin in the preservation of endothelial glycocalyx integrity and the microcirculation: a review. Ann Intensive Care. 2020;10(1):85. doi:10.1186/s13613-020-00697-1
196. Singh A, Fridén V, Dasgupta I, et al. High glucose causes dysfunction of the human glomerular endothelial glycocalyx. Am J Physiol-Ren Physiol. 2011;300(1):F40-F48. doi:10.1152/ajprenal.00103.2010
197. Lopez-Quintero SV, Cancel LM, Pierides A, Antonetti D, Spray DC, Tarbell JM. High Glucose Attenuates Shear-Induced Changes in Endothelial Hydraulic Conductivity by Degrading the Glycocalyx. PLOS ONE. 2013;8(11):e78954. doi:10.1371/journal.pone.0078954
198. Zuurbier CJ, Demirci C, Koeman A, Vink H, Ince C. Short-term hyperglycemia increases endothelial glycocalyx permeability and acutely decreases lineal density of capillaries with flowing red blood cells. J Appl Physiol. 2005;99(4):1471-1476. doi:10.1152/japplphysiol.00436.2005
199. Nenseter MS, Rustan AC, Lund-Katz S, et al. Effect of dietary supplementation with n-3 polyunsaturated fatty acids on physical properties and metabolism of low density lipoprotein in humans. Arterioscler Thromb J Vasc Biol. 1992;12(3):369-379. doi:10.1161/01.ATV.12.3.369
200. Egert S, Kannenberg F, Somoza V, Erbersdobler HF, Wahrburg U. Dietary α-Linolenic Acid, EPA, and DHA Have Differential Effects on LDL Fatty Acid Composition but Similar Effects on Serum Lipid Profiles in Normolipidemic Humans12. J Nutr. 2009;139(5):861-868. doi:10.3945/jn.108.103861
201. Stewart JW, Kaplan ML, Beitz DC. Pork with a high content of polyunsaturated fatty acids lowers LDL cholesterol in women. Am J Clin Nutr. 2001;74(2):179-187. doi:10.1093/ajcn/74.2.179
202. Wander RC, Du SH, Thomas DR. Influence of long-chain polyunsaturated fatty acids on oxidation of low density lipoprotein. Prostaglandins Leukot Essent Fatty Acids. 1998;59(2):143-151. doi:10.1016/S0952-3278(98)90093-X
203. Dougherty RM, Galli C, Ferro-Luzzi A, Iacono JM. Lipid and phospholipid fatty acid composition of plasma, red blood cells, and platelets and how they are affected by dietary lipids: a study of normal subjects from Italy, Finland, and the USA. Am J Clin Nutr. 1987;45(2):443-455. doi:10.1093/ajcn/45.2.443
204. Sherratt SCR, Dawoud H, Bhatt DL, Malinski T, Mason RP. Omega-3 and omega-6 fatty acids have distinct effects on endothelial fatty acid content and nitric oxide bioavailability. Prostaglandins Leukot Essent Fatty Acids. 2021;173:102337. doi:10.1016/j.plefa.2021.102337
205. Callow J, Summers LK, Bradshaw H, Frayn KN. Changes in LDL particle composition after the consumption of meals containing different amounts and types of fat123. Am J Clin Nutr. 2002;76(2):345-350. doi:10.1093/ajcn/76.2.345
206. 13.13: Radical Addition Reactions to Double Bonds. Chemistry LibreTexts. April 27, 2015. Accessed February 27, 2026. https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Map%3A_Organic_Chemistry_(Smith)/13%3A_Radical_Reactions/13.13%3A_Radical_Addition_Reactions_to_Double_Bonds
207. Monounsaturated and Polyunsaturated n-6 Fatty Acid–Enriched Diets Modify LDL Oxidation and Decrease Human Coronary Smooth Muscle Cell DNA Synthesis. doi:10.1161/01.ATV.17.10.2088
208. Wander RC, Du SH, Thomas DR. Influence of long-chain polyunsaturated fatty acids on oxidation of low density lipoprotein. Prostaglandins Leukot Essent Fatty Acids. 1998;59(2):143-151. doi:10.1016/S0952-3278(98)90093-X
209. Ghazali R, Mehta KJ, Bligh SA, Tewfik I, Clemens D, Patel VB. High omega arachidonic acid/docosahexaenoic acid ratio induces mitochondrial dysfunction and altered lipid metabolism in human hepatoma cells. World J Hepatol. 2020;12(3):84-98. doi:10.4254/wjh.v12.i3.84
210. Esterbauer H, Jürgens G, Quehenberger O, Koller E. Autoxidation of human low density lipoprotein: loss of polyunsaturated fatty acids and vitamin E and generation of aldehydes. J Lipid Res. 1987;28(5):495-509. doi:10.1016/S0022-2275(20)38678-8
211. Seppanen CM, Cho H, Csallany AS. Comparison between High-PUFA and Low-PUFA Fats on Lipid Peroxidation and LDL Oxidation. Food Nutr Sci. 2013;04(05):572-579. doi:10.4236/fns.2013.45074
212. Bonanome A, Pagnan A, Biffanti S, et al. Effect of dietary monounsaturated and polyunsaturated fatty acids on the susceptibility of plasma low density lipoproteins to oxidative modification. Arterioscler Thromb J Vasc Biol. 1992;12(4):529-533. doi:10.1161/01.ATV.12.4.529
213. Cicero AFG, Nascetti S, López-Sabater MC, et al. Changes in LDL Fatty Acid Composition as a Response to Olive Oil Treatment Are Inversely Related to Lipid Oxidative Damage: The EUROLIVE Study. J Am Coll Nutr. 2008;27(2):314-320. doi:10.1080/07315724.2008.10719705
214. Maingrette F, Renier G. Linoleic Acid Increases Lectin-Like Oxidized LDL Receptor-1 (LOX-1) Expression in Human Aortic Endothelial Cells. Diabetes. 2005;54(5):1506-1513. doi:10.2337/diabetes.54.5.1506
215. Endo Y, Hayashi C, Yamanaka T, et al. Linolenic Acid as the Main Source of Acrolein Formed During Heating of Vegetable Oils. J Am Oil Chem Soc. 2013;90(7):959-964. doi:10.1007/s11746-013-2242-z
216. Osório VM, de Lourdes Cardeal Z. Using SPME-GC/MS to Evaluate Acrolein Production in Cassava and Pork Sausage Fried in Different Vegetable Oils. J Am Oil Chem Soc. 2013;90(12):1795-1800. doi:10.1007/s11746-013-2338-5
217. Andreu-Sevilla AJ, Hartmann A, Burló F, Poquet N, Carbonell-Barrachina AA. Health Benefits of Using Red Palm Oil in Deep-frying Potatoes: Low Acrolein Emissions and High Intake of Carotenoids. Food Sci Technol Int. 2009;15(1):15-22. doi:10.1177/1082013208100462
218. Moumtaz S, Percival BC, Parmar D, Grootveld KL, Jansson P, Grootveld M. Toxic aldehyde generation in and food uptake from culinary oils during frying practices: peroxidative resistance of a monounsaturate-rich algae oil. Sci Rep. 2019;9(1):4125. doi:10.1038/s41598-019-39767-1
219. Fullana A, Carbonell-Barrachina AA, Sidhu S. Comparison of Volatile Aldehydes Present in the Cooking Fumes of Extra Virgin Olive, Olive, and Canola Oils. J Agric Food Chem. 2004;52(16):5207-5214. doi:10.1021/jf035241f
220. Peng CY, Lan CH, Lin PC, Kuo YC. Effects of cooking method, cooking oil, and food type on aldehyde emissions in cooking oil fumes. J Hazard Mater. 2017;324:160-167. doi:10.1016/j.jhazmat.2016.10.045
221. Savarese MD. Quantitative evaluation of the aldehydes formed in heated vegetable oils using high resolution proton-NMR spectroscopy. Riv Ital Delle Sostanze Grasse. Accessed February 27, 2026. https://www.academia.edu/31124119/Quantitative_evaluation_of_the_aldehydes_formed_in_heated_vegetable_oils_using_high_resolution_proton_NMR_spectroscopy
222. Zhang Q, Qin W, Lin D, Shen Q, Saleh ASM. The changes in the volatile aldehydes formed during the deep-fat frying process. J Food Sci Technol. 2015;52(12):7683-7696. doi:10.1007/s13197-015-1923-z
223. Ng CY, Leong XF, Masbah N, Adam SK, Kamisah Y, Jaarin K. Heated vegetable oils and cardiovascular disease risk factors. Vascul Pharmacol. 2014;61(1):1-9. doi:10.1016/j.vph.2014.02.004
224. Higashi Y, Matsuoka H, Umei H, et al. Endothelial function in subjects with isolated low HDL cholesterol: role of nitric oxide and circulating progenitor cells. Am J Physiol-Endocrinol Metab. 2010;298(2):E202-E209. doi:10.1152/ajpendo.00394.2009
225. Chen Y, Arnal-Levron M, Hullin-Matsuda F, et al. In vitro oxidized HDL and HDL from type 2 diabetes patients have reduced ability to efflux oxysterols from THP-1 macrophages. Biochimie. 2018;153:232-237. doi:10.1016/j.biochi.2018.04.018
226. Nagano Y, Arai H, Kita T. High density lipoprotein loses its effect to stimulate efflux of cholesterol from foam cells after oxidative modification. Proc Natl Acad Sci. 1991;88(15):6457-6461. doi:10.1073/pnas.88.15.6457
227. Nakanishi S, Vikstedt R, Söderlund S, et al. Serum, but not monocyte macrophage foam cells derived from low HDL-C subjects, displays reduced cholesterol efflux capacity. J Lipid Res. 2009;50(2):183-192. doi:10.1194/jlr.M800196-JLR200
228. Zhang S, Ritter L, Ibragimov A. Foam cell formation in atherosclerosis: HDL and macrophage reverse cholesterol transport. Discrete Contin Dyn Syst. 2013;Supplements Volume:825-835.
229. Hayek T, Ito Y, Azrolan N, et al. Dietary fat increases high density lipoprotein (HDL) levels both by increasing the transport rates and decreasing the fractional catabolic rates of HDL cholesterol ester and apolipoprotein (Apo) A-I. Presentation of a new animal model and mechanistic studies in human Apo A-I transgenic and control mice. J Clin Invest. 1993;91(4):1665-1671. doi:10.1172/JCI116375
230. Bhanpuri NH, Hallberg SJ, Williams PT, et al. Cardiovascular disease risk factor responses to a type 2 diabetes care model including nutritional ketosis induced by sustained carbohydrate restriction at 1 year: an open label, non-randomized, controlled study. Cardiovasc Diabetol. 2018;17(1):56. doi:10.1186/s12933-018-0698-8
231. Mooradian AD, Haas MJ, Wong NCW. The Effect of Select Nutrients on Serum High-Density Lipoprotein Cholesterol and Apolipoprotein A-I Levels. Endocr Rev. 2006;27(1):2-16. doi:10.1210/er.2005-0013
232. Wolf G. High-Fat, High-Cholesterol Diet Raises Plasma Hdl Cholesterol: Studies on the Mechanism of This Effect. Nutr Rev. 1996;54(1):34-35. doi:10.1111/j.1753-4887.1996.tb03772.x
233. Siri PW, Krauss RM. Influence of dietary carbohydrate and fat on LDL and HDL particle distributions. Curr Atheroscler Rep. 2005;7(6):455-459. doi:10.1007/s11883-005-0062-9
234. Alzahrani AH, Skytte MJ, Samkani A, et al. Effects of a Self-Prepared Carbohydrate-Reduced High-Protein Diet on Cardiovascular Disease Risk Markers in Patients with Type 2 Diabetes. Nutrients. 2021;13(5):5. doi:10.3390/nu13051694
235. Laufs U. Beyond lipid-lowering: effects of statins on endothelial nitric oxide. Eur J Clin Pharmacol. 2003;58(11):719-731. doi:10.1007/s00228-002-0556-0
236. Gorabi AM, Kiaie N, Hajighasemi S, et al. Statin-Induced Nitric Oxide Signaling: Mechanisms and Therapeutic Implications. J Clin Med. 2019;8(12):2051. doi:10.3390/jcm8122051
237. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-1722. doi:10.1056/NEJMoa1615664
238. van Bruggen FH, Luijendijk HJ. Evolocumab’s Long-Term Mortality Risk Unclear Due to Shortened Follow-Up of FOURIER. Am J Cardiovasc Drugs. 2022;22(1):5-8. doi:10.1007/s40256-021-00480-y
239. Erviti J, Wright J, Bassett K, et al. Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data. BMJ Open. 2022;12(12):e060172. doi:10.1136/bmjopen-2021-060172
240. Jiang M, Gao Y, Wang K, Huang L. Lipid profile in girls with precocious puberty: a systematic review and meta-analysis. BMC Endocr Disord. 2023;23(1):225. doi:10.1186/s12902-023-01470-8
241. Eissa MA, Mihalopoulos NL, Holubkov R, Dai S, Labarthe DR. Changes in Fasting Lipids during Puberty. J Pediatr. 2016;170:199-205. doi:10.1016/j.jpeds.2015.11.018
242. Dobashi K. Changes in Serum Cholesterol in Childhood and its Tracking to Adulthood. J Atheroscler Thromb. 2022;29(1):5-7. doi:10.5551/jat.ED163
243. Ginsburg BE, Zetterström R. Serum Cholesterol Concentrations in Newborn Infants with Gestational Ages of 28–42 Weeks. Acta Paediatr. 1980;69(5):587-592. doi:10.1111/j.1651-2227.1980.tb07326.x
244. Descamps OS, Bruniaux M, Guilmot PF, Tonglet R, Heller FR. Lipoprotein concentrations in newborns are associated with allelic variations in their mothers. Atherosclerosis. 2004;172(2):287-298. doi:10.1016/j.atherosclerosis.2003.11.002
245. Yu-Poth S, Yin D, Zhao G, Kris-Etherton PM, Etherton TD. Conjugated Linoleic Acid Upregulates LDL Receptor Gene Expression in HepG2 Cells. J Nutr. 2004;134(1):68-71. doi:10.1093/jn/134.1.68
246. Cho BHS, Dokko RC, Chung BH. Oleic, linoleic and linolenic acids enhance receptor-mediated uptake of low density lipoproteins in Hep-G2 cells. J Nutr Biochem. 2002;13(6):330-336. doi:10.1016/S0955-2863(02)00174-2
247. Yu-Poth S, Yin D, Kris-Etherton PM, Zhao G, Etherton TD. Long-Chain Polyunsaturated Fatty Acids Upregulate LDL Receptor Protein Expression in Fibroblasts and HepG2 Cells. J Nutr. 2005;135(11):2541-2545. doi:10.1093/jn/135.11.2541
248. Ramsden CE, Zamora D, Leelarthaepin B, et al. Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis. The BMJ. 2013;346:e8707. doi:10.1136/bmj.e8707
249. Woodhill JM, Palmer AJ, Leelarthaepin B, McGilchrist C, Blacket RB. Low Fat, Low Cholesterol Diet in Secondary Prevention of Coronary Heart Disease. In: Kritchevsky D, Paoletti R, Holmes WL, eds. Drugs, Lipid Metabolism, and Atherosclerosis. Advances in Experimental Medicine and Biology. Springer US; 1978:317-330. doi:10.1007/978-1-4684-0967-3_18
250. Gruppen EG, Riphagen IJ, Connelly MA, Otvos JD, Bakker SJL, Dullaart RPF. GlycA, a Pro-Inflammatory Glycoprotein Biomarker, and Incident Cardiovascular Disease: Relationship with C-Reactive Protein and Renal Function. Shimosawa T, ed. PLOS ONE. 2015;10(9):e0139057. doi:10.1371/journal.pone.0139057
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