The Problematic Paradigm of LDL-C, Part 9

Part 9 - An Energy Delivery Model: The Downstream Consequences of an Impaired Energy Delivery System

Previous - Part 8 - An Energy Delivery Model: The Contrasting Presentations of Elevated LDL-C

Over the preceding sections, we’ve driven home a few important facts:

• There is effectively no independent relationship between LDL cholesterol and cardiovascular outcomes
• There are two major manners by which the energy delivery nature of lipid metabolism can lead to elevated LDL cholesterol

The word “independent” is emphasized because without considering factors of metabolic health, the relationship between elevated LDL-C and poor cardiovascular outcomes does exist. But it appears to exist only because the number of people with elevated LDL-C through poor metabolic health (poor triglyceride utilization, increased triglyceride return to the liver, etc.) dwarf the number of people whose LDL-C is elevated as a result of an increased demand for efficient energy delivery. Because LDL-C is far more commonly elevated in unhealthy individuals, the relationship between LDL-C and cardiovascular disease persists and cholesterol appears to be a possible culprit. But is elevated LDL-C the reason for the disease, or does it simply occur alongside the real disease process? Let’s dive in –

 

Increased Triglyceride Return to the Liver

As you’ll recall, poor triglyceride uptake at the periphery results in an extended VLDL lifespan and a preponderance of triglyceride-rich lipoproteins. These lipoproteins must offload some of their excess triglyceride burden, and do so via the CETP-mediated exchange of triglycerides to HDL and LDL particles. This “spreads out” the excess triglycerides for return to the liver.

This exchange is the reason for depressed HDL-C in metabolically unhealthy persons, but it’s the effect on LDL particles on which we’ll focus. When an LDL particle serves as the trade partner, it gives away some amount of cholesterol to the VLDL and takes on a corresponding triglyceride load. Now, both particles return to the liver to offload much of their triglyceride burden there.

This process is aided by an increased expression of the LDL receptor and increased activity of an enzyme known as hepatic lipase.^1–5 Typically, the principal role of hepatic lipase is to remove triglycerides and remodel the VLDL remnants to LDL particles, such that they may reenter the bloodstream. However in this case, because LDL particles are unusually rich in triglycerides, they too will be acted upon by hepatic lipase for triglyceride removal. While these particles didn’t change in size when they traded away cholesterol for triglycerides, they now shrink with the removal of those excess triglycerides.^5–8

 

Impact of Modified LDL Particles

Herein lies one of the major ways in which poor metabolic efficiency can elevate one’s risk for cardiovascular disease. Small, dense LDL particles (sdLDL) are significantly more prone to undesirable modification than are normal LDL particles.^9–14 This vulnerability is one of the reasons individuals with poor metabolic health, and thus more sdLDL, also have higher levels of oxidized and glycated LDL particles that ultimately help trigger an immune response (although, as we will see in a later section, diet can also lead to modification of normal sized LDL particles as well).^12–18   

Glycated and oxidized LDL particles are those that have been damaged by exposure to elevated blood sugar and oxidative stress, respectively. They, along with yet undamaged sdLDL, are collectively known as “modified LDL particles,” and are instrumental in the genesis of cardiovascular disease. These particles are the preferential target of receptors such as lectin-type oxidized LDL receptor 1, or LOX-1, which serves to bind and degrade modified LDL particles in the lining of the blood vessel.^19,20 LOX-1 activity is typically quite low, but is increased in the presence of elevated blood sugar, oxidized LDL particles, and certain inflammatory mediators.^21–27

LOX-1 acts by binding and engulfing the modified LDL particle in the vessel wall, which has multiple cascading effects. These include:

•  Increased expression of NADPH Oxidase, an often-dormant enzyme that catalyzes the formation of reactive oxygen species (“free radicals”)^28,29
•  Increased expression of the immune-modulating protein NF-kB, which plays an inflammatory role in many disease states^30–32
• Increased action, via NF-kB, of adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1) and monocyte chemoattractant protein 1 (MCP1), which aid in the signaling of immune cells to the site of the vessel-bound LDL particle^19,33–35

 

Before continuing, this is a good time to stress again that the cholesterol contained within these molecules has nothing to do with this process, and that unmodified LDL particles are not a normal target for LOX-1 binding.^19,36–39

 

Immune Activity

So what happens after LOX-1 binds a modified LDL particle and begins signaling other molecules to get involved? One main effect is the aforementioned upregulation of adhesion molecules such as VCAM1 and MCP1, which generally serve to attract and mediate the adhesion of immune cells known as macrophages to the areas of LDL particle entrapment. These macrophages can then move into the wall of the blood vessel and internalize the LDL particle, which are degraded during the formation of something known as a foam cell.^40–42

Foam cells can broadly take two paths from here. The first involves the transport of the free cholesterol from the now-degraded LDL particle to the surface of the foam cell for eventual recycling to the body.⁴³ Consider this entire process from an evolutionary perspective to understand why this is natural and likely helpful – Even in a very healthy person, some LDL particles are inevitably going to be modified or damaged, making them a target of LOX-1 and a subsequent immune response. While it might sound crazy in the context of plaque and modern heart disease, the binding of a damaged particle to the wall of the blood vessel serves an important purpose – it prevents the damaged LDL from traveling to other parts of the body and furthering oxidative damage elsewhere. With the aforementioned systems in place to capture, destroy, and recycle its components, the occasional damaged LDL particle can be sequestered and then removed from the blood vessel with no long-term damage or risk.

The second path, however, is far more sinister and may be followed when the rate of damaged particle entrapment exceeds the rate of particle removal. Foam cells themselves release macrophage retention factors that discourage migration away from the initial site of LDL entrapment and encourage further macrophage activity.^42,44,45 This promotes the proliferation of something called vascular smooth muscle cells (VSMC), the cells that form the wall of the blood vessel. Particularly in cases of significant foam cell formation, these VSMCs will help form a fibrous cap (a new vessel wall, essentially) over the site of LDL and macrophage accumulation. This blocks off the foam cells from the rest of the bloodstream, but also narrows the blood vessel itself. The progressive thickening and potential rupture of these VSMC caps are what lead to arterial blockage and other cardiovascular manifestation of disease.^46–49

Of note – the VSMC cap interferes with normal calcium regulation and encourages calcium depositions in the blood vessels that can be measured on a coronary artery calcium (CAC) scan.^50–52 A CAC scan is one of the gold standard measures of potential heart disease, as it measures narrowing and potential blockages in the vessels themselves. It is when following this second path – when the immune response to modified LDL particles exceeds the capacity to clear them – that calcium deposits are noted and significant arterial narrowing may occur.

The genesis of sdLDL is instrumental in the formation of arterial plaques and the progression of cardiovascular disease. However, it is not the only factor that increases the risk for cardiovascular events. As noted, the glycation and oxidation of normal LDL particles can contribute as well, as can a variety of other factors that we will explore in the next section.

 

**Key Takeaways

• The increase in triglyceride return to the liver results in an increased action of hepatic lipase on LDL particles, causing them to shrink in size
• sdLDL particles are particularly prone to oxidative and glycemic damage and, along with other damaged LDL particles, may be bound in the vessel wall by receptors such as LOX-1
• The binding of a modified LDL particle by LOX-1 triggers an immune response at the site of LDL entrapment, resulting in the formation of macrophage foam cells
• When the rate of foam cell and VSMC cap formation exceeds the capacity to degrade and recycle the damaged LDL particles, plaques can occur

Part 10 - Other Factors in the Development of Atherosclerosis

 

 

1.               Streicher R, Kotzka J, Müller-Wieland D, et al. SREBP-1 mediates activation of the low density lipoprotein receptor promoter by insulin and insulin-like growth factor-I. J Biol Chem. 1996;271(12):7128-7133. doi:10.1074/jbc.271.12.7128

2.               Salter AM, Fisher SC, Brindley DN. Binding of low-density lipoprotein to monolayer cultures of rat hepatocytes is increased by insulin and decreased by dexamethasone. FEBS Lett. 1987;220(1):159-162. doi:10.1016/0014-5793(87)80895-5

3.               Au DT, Strickland DK, Muratoglu SC. The LDL Receptor-Related Protein 1: At the Crossroads of Lipoprotein Metabolism and Insulin Signaling. J Diabetes Res. 2017;2017:8356537. doi:10.1155/2017/8356537

4.               Rashid S, Watanabe T, Sakaue T, Lewis GF. Mechanisms of HDL lowering in insulin resistant, hypertriglyceridemic states: the combined effect of HDL triglyceride enrichment and elevated hepatic lipase activity. Clin Biochem. 2003;36(6):421-429. doi:10.1016/s0009-9120(03)00078-x

5.               Kobayashi J, Miyashita K, Nakajima K, Mabuchi H. Hepatic Lipase: a Comprehensive View of its Role on Plasma Lipid and Lipoprotein Metabolism. J Atheroscler Thromb. 2015;22(10):1001-1011. doi:10.5551/jat.31617

6.               Jansen H, Verhoeven AJM, Sijbrands EJG. Hepatic lipase. Journal of Lipid Research. 2002;43(9):1352-1362. doi:10.1194/jlr.R200008-JLR200

7.               Brunzell JD, Zambon A, Deeb SS. The effect of hepatic lipase on coronary artery disease in humans is influenced by the underlying lipoprotein phenotype. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 2012;1821(3):365-372. doi:10.1016/j.bbalip.2011.09.008

8.               Zambon A, Austin MA, Brown BG, Hokanson JE, Brunzell JD. Effect of hepatic lipase on LDL in normal men and those with coronary artery disease. Arteriosclerosis and Thrombosis: A Journal of Vascular Biology. 1993;13(2):147-153. doi:10.1161/01.ATV.13.2.147

9.               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. Arteriosclerosis and Thrombosis: A Journal of Vascular Biology. 1992;12(5):569-583. doi:10.1161/01.ATV.12.5.569

10.             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. The American Journal of Medicine. 1993;94(4):350-356. doi:10.1016/0002-9343(93)90144-E

11.             Sobal G, Menzel J, Sinzinger H. Why is glycated LDL more sensitive to oxidation than native LDL? A comparative study. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2000;63(4):177-186. doi:10.1054/plef.2000.0204

12.             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

13.             Younis N, Charlton-Menys V, Sharma R, Soran H, Durrington PN. Glycation of LDL in non-diabetic people: Small dense LDL is preferentially glycated both in vivo and in vitro. Atherosclerosis. 2009;202(1):162-168. doi:10.1016/j.atherosclerosis.2008.04.036

14.             Younis NN, Soran H, Sharma R, et al. Small-dense LDL and LDL glycation in metabolic syndrome and in statin-treated and non-statin-treated type 2 diabetes: Diabetes and Vascular Disease Research. Published online September 27, 2010. doi:10.1177/1479164110383063

15.             Holvoet P, Lee DH, Steffes M, Gross M, Jacobs DR. Association between circulating oxidized low-density lipoprotein and incidence of the metabolic syndrome. JAMA. 2008;299(19):2287-2293. doi:10.1001/jama.299.19.2287

16.             Holvoet P, Kritchevsky SB, Tracy RP, et al. The Metabolic Syndrome, Circulating Oxidized LDL, and Risk of Myocardial Infarction in Well-Functioning Elderly People in the Health, Aging, and Body Composition Cohort. Diabetes. 2004;53(4):1068-1073. doi:10.2337/diabetes.53.4.1068

17.             Sigurdardottir V, Fagerberg B, Hulthe J. Circulating oxidized low-density lipoprotein (LDL) is associated with risk factors of the metabolic syndrome and LDL size in clinically healthy 58-year-old men (AIR study). Journal of Internal Medicine. 2002;252(5):440-447. doi:10.1046/j.1365-2796.2002.01054.x

18.             Lapointe A, Couillard C, Piché MÈ, et al. Circulating oxidized LDL is associated with parameters of the metabolic syndrome in postmenopausal women. Atherosclerosis. 2007;191(2):362-368. doi:10.1016/j.atherosclerosis.2006.03.036

19.             Twigg MW, Freestone K, Homer-Vanniasinkam S, Ponnambalam S. The LOX-1 Scavenger Receptor and Its Implications in the Treatment of Vascular Disease. Cardiology Research and Practice. 2012;2012:e632408. doi:10.1155/2012/632408

20.             Sawamura T, Wakabayashi I, Okamura T. LOX-1 in atherosclerotic disease. Clinica Chimica Acta. 2015;440:157-163. doi:10.1016/j.cca.2014.11.016

21.             Chen M, Nagase M, Fujita T, Narumiya S, Masaki T, Sawamura T. Diabetes Enhances Lectin-like Oxidized LDL Receptor-1 (LOX-1) Expression in the Vascular Endothelium: Possible Role of LOX-1 Ligand and AGE. Biochemical and Biophysical Research Communications. 2001;287(4):962-968. doi:10.1006/bbrc.2001.5674

22.             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

23.             Hofnagel O, Luechtenborg B, Stolle K, et al. Proinflammatory cytokines regulate LOX-1 expression in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2004;24(10):1789-1795. doi:10.1161/01.ATV.0000140061.89096.2b

24.             Kattoor AJ, Goel A, Mehta JL. LOX-1: Regulation, Signaling and Its Role in Atherosclerosis. Antioxidants. 2019;8(7):218. doi:10.3390/antiox8070218

25.             Rudijanto A. The Expression and Down Stream Effect of Lectin Like-oxidized Low Density Lipoprotein 1 (LOX-1) in Hyperglycemic State. Acta Med Indones. 2007;39(1):8.

26.             Renier G, Maingrette F, Li L. Diabetic Vasculopathy and the Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 (LOX-1). Current Diabetes Reviews. 2007;3(2):103-110. doi:10.2174/157339907780598225

27.             Taye A, Saad AH, Kumar AH, Morawietz H. Effect of apocynin on NADPH oxidase-mediated oxidative stress-LOX-1-eNOS pathway in human endothelial cells exposed to high glucose. European Journal of Pharmacology. 2010;627(1):42-48. doi:10.1016/j.ejphar.2009.10.045

28.             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. Molecular Nutrition & Food Research. 2011;55(S2):S227-S240. doi:10.1002/mnfr.201100147

29.             Lubrano V, Balzan S. LOX-1 and ROS, inseparable factors in the process of endothelial damage. Free Radical Research. 2014;48(8):841-848. doi:10.3109/10715762.2014.929122

30.             Quagliariello V, Bonelli A, Paccone A, et al. Oxidized Low-Density Lipoproteins increases nivolumab-induced cardiotoxicity through TLR4/NF-KB and NLRP3 pathways. European Heart Journal. 2021;42(Supplement_1):ehab724.2837. doi:10.1093/eurheartj/ehab724.2837

31.             Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1): a crucial driver of atherosclerotic cardiovascular disease | European Heart Journal | Oxford Academic. Accessed August 17, 2022. https://academic.oup.com/eurheartj/article/42/18/1797/5960181

32.             Robbesyn F, Salvayre R, Negre-Salvayre A. Dual Role of Oxidized LDL on the NF-KappaB Signaling Pathway. Free Radical Research. 2004;38(6):541-551. doi:10.1080/10715760410001665244

33.             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. Molecular and Cellular Biology. 1993;13(10):6283-6289. doi:10.1128/mcb.13.10.6283-6289.1993

34.             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.

35.             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/

36.             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

37.             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

38.             Review. 1996;34(8):599-608. doi:10.1515/cclm.1996.34.8.599

39.             Keidar S, Kaplan M, Aviram M. Angiotensin II–Modified LDL Is Taken Up by Macrophages Via the Scavenger Receptor, Leading to Cellular Cholesterol Accumulation. Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16(1):97-105. doi:10.1161/01.ATV.16.1.97

40.             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

41.             Galkina E, Ley K. Vascular adhesion molecules in atherosclerosis. Arterioscler Thromb Vasc Biol. 2007;27(11):2292-2301. doi:10.1161/ATVBAHA.107.149179

42.             Moore K, Sheedy F, Fisher E. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol. 2013;13(10):709-721. doi:10.1038/nri3520

43.             Yu XH, Fu YC, Zhang DW, Yin K, Tang CK. Foam cells in atherosclerosis. Clinica Chimica Acta. 2013;424:245-252. doi:10.1016/j.cca.2013.06.006

44.             Shiratsuch H, Basson MD. Differential regulation of monocyte/macrophage cytokine production by pressure. The American Journal of Surgery. 2005;190(5):757-762. doi:10.1016/j.amjsurg.2005.07.016

45.             Fadok V, McDonald P, Bratton D, Henson P. Regulation of macrophage cytokine production by phagocytosis of apoptotic and post-apoptotic cells. Biochemical Society transactions. 1998;26:653-656. doi:10.1042/bst0260653

46.             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

47.             Niu C, Wang X, Zhao M, et al. Macrophage Foam Cell–Derived Extracellular Vesicles Promote Vascular Smooth Muscle Cell Migration and Adhesion. Journal of the American Heart Association. 5(10):e004099. doi:10.1161/JAHA.116.004099

48.             Boyle JJ. Macrophage Activation in Atherosclerosis: Pathogenesis and Pharmacology of Plaque Rupture. Current Vascular Pharmacology. 2005;3(1):63-68. doi:10.2174/1570161052773861

49.             HEREMBERT T, GOGUSEV J, ZHU DL, DRUEKE TB, MARCHE P. Control of vascular smooth-muscle cell growth by macrophage-colony-stimulating factor. Biochemical Journal. 1997;325(1):123-128. doi:10.1042/bj3250123

50.             Fakhry M, Roszkowska M, Briolay A, et al. TNAP stimulates vascular smooth muscle cell trans-differentiation into chondrocytes through calcium deposition and BMP-2 activation: Possible implication in atherosclerotic plaque stability. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2017;1863(3):643-653. doi:10.1016/j.bbadis.2016.12.003

51.             Stary HC. The development of calcium deposits in atherosclerotic lesions and their persistence after lipid regression. The American Journal of Cardiology. 2001;88(2, Supplement 1):16-19. doi:10.1016/S0002-9149(01)01713-1

52.             Pugliese G, Iacobini C, Fantauzzi CB, Menini S. The dark and bright side of atherosclerotic calcification. Atherosclerosis. 2015;238(2):220-230. doi:10.1016/j.atherosclerosis.2014.12.011

 

Setbacks

  

Looking Back

About five months ago I first started detailing my recovery here when I finally ran six (easy) miles at the semi-arbitrary pace of 10 minutes per mile. About two months after that, I was running 9 minute pace at the same effort. I had hit fifty miles in a week on a couple occasions, and had pushed the “long” run out to twelve miles. Things seemed to be going fairly well, or at least continuing to progress in the desired direction.

The entire time, though, the symptoms that had improved to the point that I could run had remained more or less “stuck” in that same place. I still suffered from headaches, neck pain, and numbness in my limbs on a daily basis. Failure to wear my neck brace when sitting down still threatened to ruin my day. Many runs, especially those at the end of a taxing day, could only be achieved after a lengthy mental battle to drag myself out the door. Often times, I lost that battle and just went to sleep instead. When I did run, the numbness and (depending on how bad the day or week had been) impaired motor control would inevitably fade, only to return all the same after the run or the next morning.

About five weeks ago I had covid again. The illness itself was a nonissue – extremely mild and leaving no lasting symptoms. In fact, after the first day or two I felt really legitimately good – My persistent neurological symptoms were reduced or absent. While this was great in a vacuum, it also forced me to confront reality – No longer could I persist under the illusion that running was having no negative impact on my symptoms, or that I was still slowly improving with time. Starting to jog again after a week and half off confirmed this, as the numbness and other symptoms came creeping back in. Certainly some of this was the result of increasing daily activity – driving, working, etc. – as well, but the fact remained that total rest had greatly moderated my symptoms, only for them to come rushing back.

So after only a few runs back, I quit again. And I bottomed out for a few days – buffalo chicken dip, Chipotle, ice cream. This emotional foray into culinary degeneracy frankly made me feel like shit, seemingly confirming that diet and food still play a large role in my symptoms as well. Since then, I’m about a week and half back on a pure beef, salmon, and salt diet. I haven’t run in that time or exercised much at all, but I feel pretty great. Normal, really. Just not normal enough to quite live a normal life yet.

Moving Forward

So what now? Well, certainly the plan is to be far more diligent with diet moving forward. My remarkable progress after experimenting with a carnivore diet and extended fasting got me close enough to functional that I could pretend everything was normal. I had started adding fruit to help with the running, and things mostly seemed good for a while. But I relaxed here and there over the following weeks – things like dairy, coffee, plantains. Things I didn’t need to be eating and things I was convincing myself weren’t causing any problems (and perhaps certain ones weren’t, I have no idea). Much like I was convincing myself running wasn’t causing any problems.

So now the plan is to double down, reset, and refocus my efforts for the next attempt. As mentioned, I’m ~10 days back on a pure carnivore diet and plan to remain that way for some time. The immediate plan, beginning tomorrow, is to undertake another extended fast. Something in the one week range again, hopefully, or maybe longer. I don’t know if I can expect such a remarkable outcome this time, as thankfully I start from a much better place. But I do hope some progress towards repairing this lasting damage can be made.

I fully expect to be one hundred percent symptom-free following the fast, as I’m already largely that way now. Then we basically hope it stays that way as I ease back in. Low and slow – Lots of hiking around, some shuffling here and there, light jogging, and so forth. Fingers crossed in a handful of weeks I’ll be running fairly regularly without any neurological symptoms impacting my ability to exercise or live my life. That’s asking a lot, of course, as I’ve been messed up for two years straight at this point and it feels almost beyond belief that it could ever really go away for good.

It is the goal, though. And more than that, it is absolutely the intent. I’ve still got a lot of racing to do…

The Problematic Paradigm of LDL-C, Part 8

Part 8 - An Energy Delivery Model: The Contrasting Presentations of Elevated LDL-C

Previous - Part 7 - An Energy Delivery Model: Efficient Triglyceride Uptake and An Increased Energy Demand

In the previous sections, we have discussed how triglycerides move through and are used by the body. While traditional paradigms suggest that it is almost entirely fat consumption that influences lipid profiles, we have seen the two major ways in which an energy delivery model better explains lipid behavior:

1 - Poor energy utilization by the cells causes excess triglycerides to return to the liver

2 – An increased reliance on stored body fat increases VLDL production in order to meet energy demands

The first example is a failure of the energy delivery system, in which energy being delivered can’t be properly stored or used. The second is robust utilization of the energy delivery system. In each case, energy delivery (that is, VLDL production) is increased. I’ll pull passages from my paper on the topic to further drive home how significant these difference are:

 

“The more common presentation of elevated LDL-C, and the one that continues to prop up the lipid-heart hypothesis, is that of an insulin-resistant individual with poor metabolic efficiency. This individual is often overweight or obese, often largely sedentary, and almost certainly overconsumes carbohydrates. Because this person frequently overconsumes carbohydrates, post-prandial triglycerides will often be elevated. Poor metabolic flexibility and insulin resistant downregulation of LPL leads to lengthier lipemia and poor triglyceride uptake. As such, chylomicrons must “trade away” triglycerides to HDL and LDL before hepatic uptake. This causes HDL-C to be decreased and LDL to become a greater target for hepatic lipase activity. The same pattern is observed with VLDL-triglycerides, which are poorly taken up at the periphery and inevitably exchanged for cholesterol, continuing to depress HDL-C and create triglyceride-rich LDL. VLDL production is also higher than desired, the result of hepatic insulin resistance, an increased flow of glucose to the liver, and increased hepatic triglyceride return. The elevated VLDL production, and thus elevated VLDL-C, eventually manifests in increased remodeling to LDL and therefore elevated LDL-C. Furthermore, because so many LDL particles are increasingly rich in triglycerides, they are inevitably acted on by hepatic lipase and recycled into the bloodstream as small, dense LDL. Thus, due to high chylomicron and VLDL production, poor triglyceride uptake, and frequent use of HDL as a trade partner, the resultant lipid profile is legitimately concerning – Low HDL-C, high triglycerides, and, yes, high LDL-C.”

 

This, in many words, describes the metabolically unhealthy person who sees their LDL-C rise due to an impairment of their energy (that is to say, triglyceride) delivery system. As we’ll see later and as is hinted above, this presentation of elevated LDL-C is associated with many negative health risks and markers.

Contrast the above with the metabolically healthy, low-carb individual who sees their LDL-C rise due to increased (efficient) utilization of the same energy delivery system. This person’s elevated LDL-C is not associated with any of these metabolic risks or ominous health markers:

 

“The less common presentation of elevated LDL-C, the one that cannot be explained by the lipid-heart hypothesis, is that of an insulin-sensitive individual with highly efficient lipid metabolism. This person is less likely to be overweight, more likely to be active, and, most crucially, consumes few carbohydrates. Because insulin sensitivity and the capacity to use fatty acids for energy are maintained, chylomicron-triglycerides (which will likely be lower in this case) are efficiently taken up at the periphery. Endogenous triglycerides are also taken up efficiently, and the VLDL that carry them are quickly turned over to form LDL. Because excess triglycerides do not persist in blood, there is no need to rely on HDL or LDL as a receptor. HDL-C levels are maintained and triglyceride-poor LDL, not subject to hepatic lipase activity, will remain larger and more buoyant. In fact, hepatic lipase activity will remain low in general, as insulin levels are low and there are very few triglycerides being returned to the liver. However, because this individual is not overconsuming calories or consuming many carbohydrates, they will be more reliant on endogenous triglycerides as a source of energy. This increases VLDL production but, in contrast to the first example, the VLDL-triglycerides are taken up efficiently and the VLDL are remodeled very quickly. Thus, despite an increased production of cholesterol-containing VLDL, measured VLDL-C and remnant cholesterol will remain relatively low. Instead, this increased production will manifest as elevated LDL-C, due to the much lengthier lifespan of the LDL particle. The resultant profile also features elevated LDL-C, but in this case is not of the same concern, as evidenced by low triglycerides levels, low remnant cholesterol, high HDL-C, and large, buoyant LDL particles.”

 

Below is a modified table from that same paper, outlining the two distinct presentations of elevated LDL-C and comparing them to a metabolically healthy person consuming some reasonable amount of carbohydrates. Note that “sdLDL” refers to the formation of the smaller LDL particles that were described in the prior section on inefficient triglyceride utilization. While cardiovascular risk is included in the table, it is not yet necessary to understand what causes disease risk to be increased, as that will be a future topic in this series.

 

	Poor Metabolic Health	Healthy Moderate Carb	Healthy Low/Zero Carb
Presentation	Overconsumption of carbohydrates, poor metabolic health, potentially overweight and/or inactive	Reasonable carbohydrate consumption, much more likely to be active and at a healthy weight, good metabolic health	Zero or near-zero carbohydrate consumption, good metabolic health
Insulin Levels	Chronically Elevated	Low to moderate	Low
VLDL Production	Increase in TG-rich VLDL due to return of excess triglycerides to the liver	No increase in VLDL	Increase in TG-rich VLDL due to reliance on stored body fat for energy
VLDL Utilization	Poor, leading to increased VLDL lifespan and TGRL	Good to excellent	Excellent
LDL-C	Increases secondary to increased VLDL production	No increase	Increases secondary to increased VLDL production
sdLDL	Preponderance of TGRL increases CETP activity and TG-rich LDL, which are hydrolyzed to sdLDL	Little to no genesis of sdLDL	Little to no genesis of sdLDL
CVD risk	Elevated, due to sdLDL and hyperglycemic/insulin-resistant environment. Highlighted by high TG/HDL ratio and other markers	Not elevated	Not elevated, due to lack of sdLDL/hyperglycemia/ insulin-resistance. Highlighted by low TG/HDL ratio and other markers

Part 9 - An Energy Delivery Model: The Downstream Consequences of an Impaired Energy Delivery System

The Problematic Paradigm of LDL-C, Part 7

Part 7 - An Energy Delivery Model: Efficient Triglyceride Uptake and An Increased Energy Demand

Previous - Part 6 - An Energy Delivery Model: The Consequences of Poor Triglyceride Utilization

In the previous section, we discussed the causes and consequences of poor triglyceride utilization by the cells of the body, and the way in which this can lead to elevated LDL cholesterol. In this case, it was poor uptake of triglycerides and subsequent return of excess triglycerides to the liver that led to a compensatory increase in VLDL production. These excess cholesterol-containing VLDL particles inevitably convert to LDL, leading to an increase in measured LDL cholesterol.

This is, however, not the only way by which increased VLDL production can lead to elevated LDL-C. While the previous example outlined VLDL production driven by metabolic dysfunction, VLDL and LDL increases can be seen for, effectively, the opposite reason as well.

Efficient Triglyceride Metabolism

In an individual with more optimal metabolic health, the fate of a VLDL particle and the triglycerides within is different. The frequently elevated blood glucose and chronically elevated insulin of a person who overconsumes carbohydrates leads to an overreliance on carbohydrates for energy, while the absence of these issues allows greater utilization of triglycerides instead. Greater lipoprotein lipase (LPL) activity and the flexibility to utilize fatty acids for energy means triglycerides are more effectively liberated from VLDL at the body’s fat and muscle cells.^1–3 As a result, VLDL lifespan is decreased in a healthy person and the triglyceride rich lipoproteins (TGRL) that characterize the unhealthy person’s metabolism are largely absent.

Recall the downstream effects of increased VLDL lifespan and the proliferation of TGRL – In these instances, CETP mediates a trade of triglycerides from VLDL particles to HDL and LDL particles to help facilitate return of triglycerides to the liver. This process reduces HDL cholesterol and ultimately shrinks HDL and LDL particles. In a person with good metabolic health and few TGRL, this trade is largely unnecessary - The VLDL remnant particles return to the liver with whatever triglycerides they retain without needing to share the burden with HDL and LDL particles.^4,5

This can be identified on a standard lipid panel by the presence of lower triglycerides and lower VLDL cholesterol, the result of efficient triglyceride uptake and a short VLDL lifespan. This desirable metabolic efficiency can be maintained across a range of non-excessive carbohydrate intake. Whether a person consumes no carbohydrates at all or consumes a moderate amount in the context of a healthy-weight, active lifestyle, reasonably efficient uptake of triglycerides will be maintained and the deleterious effects of poor fatty acid metabolism avoided if carbohydrate consumption is moderated relative to energy needs.^6–10 The effects of overconsumption, of course, are explained in the previous section.

Reliance on VLDL for Energy Delivery

What does any of this have to do with elevated LDL cholesterol? Consider the more extreme instances of carbohydrate restriction, which can generally be achieved two ways – through regular or extended fasting, or through a long-term low carbohydrate diet. In either case, the effects are basically the same; long-term stable blood sugar avoids the need to burn carbohydrates for energy as a means of regulating blood sugar levels. Meanwhile, chronically low insulin levels means enzymes such as hormone-sensitive lipase (HSL - which is inhibited by insulin) are consistently active in breaking down stored body fat – fatty acids which travel back to the liver to be packaged as triglycerides in VLDL particles.^11–15 Simultaneous elevated use of fatty acids for energy and break down of stored body fat increases the number of VLDL particles being produced to traffic triglycerides to cells of the body.

This is the same outcome – increased VLDL production – we described in the previous section. The context, though, is entirely different. While the unhealthy person is increasing VLDL production to compensate for poor energy utilization and increased triglyceride return to the liver, the healthy low-carb person is increasing VLDL production to match an increased efficient use of triglycerides for energy. Because the VLDL particles being produced to meet this need also contain cholesterol, they ultimately become LDL particles that still contain that same cholesterol. LDL cholesterol thus rises, while the quick uptake of triglycerides and short lifespan of the VLDL particles means that measured triglycerides and VLDL cholesterol remain low.

This is an important point – even though this person is producing “extra” VLDL-triglycerides, their measured triglyceride levels will be low. Increasing triglyceride levels do not reflect increased production, but instead decreased utilization. It is the poor uptake of triglycerides and the lengthy lifespan of VLDL particles that contain them that causes triglyceride levels to rise in a metabolically unhealthy person. But regardless of the root cause, the increased VLDL production ultimately leads to increased LDL cholesterol levels, as the cholesterol containing VLDL particles turn over to LDL particles in both cases. In the next section, we’ll further explore the contextual differences between these two disparate cases of elevated LDL cholesterol.

**Key Takeaways:

• Very low insulin levels that result from fasting or a low-carbohydrate diet result in consistent action of hormone-sensitive lipase in breaking down stored body fat
• Fatty acids freed from the body’s stores are transported back to the liver and packaged in VLDL particles
• This increase in VLDL production is matched by increased triglyceride utilization by the body’s cells, keeping measured triglyceride levels low
• The increase in cholesterol containing VLDL particles leads to an increase in LDL cholesterol as the VLDL quickly turn over to LDL particles

Part 8 - An Energy Delivery Model: The Contrasting Presentations of Elevated LDL-C

 

1.           Panarotto D, Rémillard P, Bouffard L, Maheux P. Insulin resistance affects the regulation of lipoprotein lipase in the postprandial period and in an adipose tissue-specific manner. Eur J Clin Invest. 2002;32(2):84-92. doi:10.1046/j.1365-2362.2002.00945.x

2.           Taskinen MR, Nikkilä EA, Kuusi T, Harno K. Lipoprotein lipase activity and serum lipoproteins in untreated Type 2 (insulin-independent) diabetes associated with obesity. Diabetologia. 1982;22(1):46-50. doi:10.1007/BF00253869

3.           Miyashita Y, Shirai K. Clinical Determination of the Severity of Metabolic Syndrome: Preheparin Lipoprotein Lipase Mass as a New Marker of Metabolic Syndrome. Current Medicinal Chemistry - Cardiovascular & Hematological Agents. 2005;3(4):377-381. doi:10.2174/156801605774322292

4.           Mann CJ, Yen FT, Grant AM, Bihain BE. Mechanism of plasma cholesteryl ester transfer in hypertriglyceridemia. J Clin Invest. 1991;88(6):2059-2066. doi:10.1172/JCI115535

5.           Rashid S, Sniderman A, Melone M, et al. Elevated cholesteryl ester transfer protein (CETP) activity, a major determinant of the atherogenic dyslipidemia, and atherosclerotic cardiovascular disease in South Asians. Eur J Prev Cardiol. 2015;22(4):468-477. doi:10.1177/2047487314528461

6.           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

7.           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

8.           Freedland SJ, Howard LE, Ngo A, et al. Low Carbohydrate Diets and Estimated Cardiovascular and Metabolic Syndrome Risk in Prostate Cancer. Journal of Urology. 2021;206(6):1411-1419. doi:10.1097/JU.0000000000002112

9.           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

10.         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. Cardiovascular Diabetology. 2022;21(1):138. doi:10.1186/s12933-022-01571-z

11.         Carey GB. Mechanisms Regulating Adipocyte Lipolysis. In: Richter EA, Kiens B, Galbo H, Saltin B, eds. Skeletal Muscle Metabolism in Exercise and Diabetes. Advances in Experimental Medicine and Biology. Springer US; 1998:157-170. doi:10.1007/978-1-4899-1928-1_15

12.         Frühbeck G, Méndez-Giménez L, Fernández-Formoso JA, Fernández S, Rodríguez A. Regulation of adipocyte lipolysis. Nutrition Research Reviews. 2014;27(1):63-93. doi:10.1017/S095442241400002X

13.         Kraemer FB, Shen WJ. Hormone-sensitive lipase. Journal of Lipid Research. 2002;43(10):1585-1594. doi:10.1194/jlr.R200009-JLR200

14.         Spector AA. Fatty acid binding to plasma albumin. Journal of Lipid Research. 1975;16(3):165-179. doi:10.1016/S0022-2275(20)36723-7

15.         Alves-Bezerra M, Cohen DE. Triglyceride metabolism in the liver. Compr Physiol. 2017;8(1):1-8. doi:10.1002/cphy.c170012