Part 5 - An Energy Delivery Model: Triglyceride Production and Utilization
Previous - Part 4 - Lipids and Cholesterol: Who Are the Players and What Are We Really Measuring?
The body’s internal cholesterol pathway begins with production
of VLDL in the liver. VLDL, very low-density lipoproteins, are the larger
precursor to the more famous low-density lipoprotein molecule (LDL). Like all lipoproteins,
VLDL are composed of a phospholipid shell and contain primarily two items of
note – cholesterol and triglycerides. Lipoproteins also contain special
proteins embedded in their outer shell, known as apolipoproteins. VLDL (and
LDL) contain a signature apolipoprotein, apoB100, that distinguishes them from
other lipoprotein classes.
The major role VLDL production plays is to move about the
bloodstream the triglycerides and cholesterol contained within, and it’s the triglycerides
we’ll focus on in explaining the observed effects of diet and lifestyle on
cholesterol levels. Triglycerides do not receive quite the same fanfare as the “bad”
LDL-cholesterol, but they are a very important component of the standard lipid
panel, a useful marker of metabolic health, and, as I’ll attempt to
demonstrate, a primary driver of lipid behavior in the human body.
First, an important overview of energy – The human body can produce
ATP, the molecule your cells actually use to fuel bodily processes, from either
fat or carbohydrate. However, while fat and carbohydrate can both be used for
energy, there are major differences in the way your body handles the consumption
and storage of the two. Carbohydrate levels (glucose) in the blood are tightly
regulated. Generally, an increase in blood glucose is met by a corresponding
increase in the storage hormone insulin, which acts to lower glucose levels
back towards baseline. Some of the excess glucose will be used immediately to
produce ATP, but not all of it can be used at once. The rest has to be stored.
However, storage capacity for glucose (termed “glycogen” in its stored form) in
the muscles and in the liver is somewhat limited. That which cannot be used or
stored as glycogen will ultimately be converted into triglycerides by a process
known as de novo lipogenesis.1 We’ll touch on
that process in more detail in later sections, but for now its sufficient to
know that excess carbohydrates are converted into fat in the form of
triglycerides.
Storage of fat, on the other hand, is effectively unlimited.
This can be confirmed by looking around just about anywhere in western society.
Both excess dietary fat and excess carbohydrate (that cannot be stored as
glycogen) are ultimately stored as body fat. For those reasons (among others) –
that fat storage is unlimited and that excess carbs are converted to fat – one
could easily argue that fat, not carbohydrates, are the body’s “preferred”
source of fuel, despite wide spread disagreement from recognizable sources.2 Regardless, what is indisputable
is that all excess fuel sources are ultimately converted to triglycerides, and
that triglycerides traveling the bloodstream aboard VLDL offer a potential
source of fuel to the cells of the body.
When VLDL leave the liver and travel to the body’s
peripheral cells, they may offload some of their triglycerides to either adipose
(fat) cells or muscles cells, both of which can express the aptly named VLDL-receptor
on their surface. This process is mediated by an enzyme known as lipoprotein lipase
(LPL) and, at muscle cells for example, results in the triglycerides being
liberated to free fatty acids for use in the production of ATP.3
In a metabolically healthy person, a good number of
triglycerides will be offloaded either to fat or muscle cells in a reasonably quick
amount of time – a VLDL particle may have a lifespan of only an hour or two.4 At this point, the VLDL remnant,
known as intermediate-density lipoprotein (IDL), can return to the liver. These
particles are taken up by the liver, aided by the LDL-receptor on the liver’s
surface, and may then have excess triglycerides removed before reentering the
bloodstream as an LDL particle.5 The removal of triglycerides along
the VLDL-IDL-LDL pathway is a key distinguishing characteristic of these particle
types. While VLDL are relatively triglyceride-rich, LDL are triglyceride-poor while
remaining, comparatively speaking, rich in cholesterol. Unlike VLDL, LDL
particles have a lifespan of multiple days.4 This is largely the reason “LDL”
has become somewhat synonymous with “cholesterol” – their longer lifespan means
that most cholesterol-containing particles at any given time are of the LDL
variety.
From this, one thing should be very clear – A person’s
LDL-cholesterol is first and foremost a reflection of their VLDL production. In
order for LDL-C to ultimately be elevated, a person needs to be producing more
VLDL particles that contain more overall cholesterol and subsequently turn into
more LDL particles (still containing the extra cholesterol).
But if LDL-C is a reflection of VLDL production, then what
drives VLDL production in the first place? An energy delivery model of lipid
metabolism posits that there can generally be two reasons:
1.
An excess of triglycerides in the liver
2.
An increased demand for triglycerides as an energy
source
Note that in stark contrast to the standard diet-heart
hypothesis, neither of these mechanisms propose that fat consumption is itself
a driver of VLDL production. That is not to say that fat consumption and diet
in general plays no role in VLDL production and thus LDL-cholesterol levels.
However, an energy delivery model proposes that reality is far more complicated
than “dietary fat consumption à
increased LDL-C.” In fact, we’ll eventually explore examples in which increased
fat consumption results in pronounced decreases in LDL-C, depending on
which of the above mechanisms was actually responsible for the initial increase.
These mechanisms are effectively at odds with one another,
and typically occur in individuals with starkly different metabolic health
profiles. It is the first, an excess of triglycerides being offloaded by the
liver, that we’ll explore next, and that largely explains the association
between elevated LDL-C levels and cardiovascular disease.
**Key takeaways:
· Triglycerides
are the primary storage form of fat and energy in the body.
· VLDL
are produced by the liver carrying triglycerides and cholesterol for delivery
to the cells of the body, and become LDL particles after offloading triglycerides.
· The
much longer lifespan of LDL particles means that LDL-C is most accurately a
reflection of VLDL production
· An
energy delivery model of lipid metabolism postulates that the movement of triglycerides
best explains lipid behavior and LDL-C levels.
1. 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
2. Choose your carbs wisely. Mayo
Clinic. Accessed January 8, 2023.
https://www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/in-depth/carbohydrates/art-20045705
3. Goudriaan JR, Santo SMSE, Voshol
PJ, et al. The VLDL receptor plays a major role in chylomicron metabolism by
enhancing LPL-mediated triglyceride hydrolysis. Journal of Lipid Research.
2004;45(8):1475-1481. doi:10.1194/jlr.M400009-JLR200
4. Millar JS, Lichtenstein AH,
Cuchel M, et al. Impact of age on the metabolism of VLDL, IDL, and LDL
apolipoprotein B-100 in men. Journal of Lipid Research.
1995;36(6):1155-1167. doi:10.1016/S0022-2275(20)41124-1
5. Zanoni P, Velagapudi S, Yalcinkaya M, Rohrer L, von Eckardstein A. Endocytosis of lipoproteins. Atherosclerosis. 2018;275:273-295. doi:10.1016/j.atherosclerosis.2018.06.881
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