The Problematic Paradigm of LDL-C, Part 6

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

Previous - Part 5 - An Energy Delivery Model: Triglyceride Production and Utilization

In the last section, we learned that triglycerides are the body’s primary storage form of fat and energy, and are packaged by the liver in VLDL particles for trafficking to the cells of the body. Next, we’ll look at what happens when this process becomes faulty or inefficient, and how this leads to elevated LDL-C levels.

Poor Triglyceride Uptake

When VLDL travel from the liver to the peripheral cells of the body, triglycerides may be offloaded either to adipose (fat) cells for storage or the muscle cells for energy production. However, a number of factors can cause this to happen at a reduced rate, such that triglyceride-rich VLDL continue to exist longer than they otherwise might.

Perhaps the most significant of these factors is insulin resistance, in which the cells of the body become less sensitive to the effects of the storage hormone insulin. This can be thought of almost the same way as a caffeine habit – one cup of coffee used to have you wired, now you need two just to get out of bed. Basically, repeated and prolonged exposure dulls the effects. In those people with poor metabolic health, insulin levels will reach greater peaks and remain elevated longer in order to achieve the same outcome.

When the cells’ sensitivity for insulin begins failing to keep up, the effects of insulin become muted. One of these effects is the expression of lipoprotein lipase (LPL), the enzyme responsible for freeing triglycerides from VLDL. Normally stimulated by the presence of insulin, LPL expression is decreased in an insulin resistant individual and triglycerides are now ineffectively freed from VLDL.^1–3 Insulin resistance also affects the uptake of triglycerides into fat cells, which themselves can become insulin resistant, especially in overweight or obese individuals with excess body fat. Remember, insulin is first and foremost a storage hormone. As your fat reserves increase, fat cells will generally become less responsive to further intake.^4,5

LPL expression is also decreased in the presence of excess blood sugar. This is perhaps fairly intuitive – when excess glucose exists in the blood, its use and storage will be favored in an effort to return blood sugar levels to normal. As a result, LPL expression is decreased and triglycerides are liberated from VLDL at a reduced rate. As we’ll eventually see, this explains much of the seemingly paradoxical observation that triglycerides in the blood are elevated to a greater degree after carbohydrate consumption than after fat consumption.^2,6

So, through a variety of potential mechanisms, triglycerides may not be effectively offloaded to the cells of the body. When this happens, the lifespan of the still triglyceride-rich VLDL (known as TGRL – triglyceride-rich lipoproteins) increases.^7–9 This raises an important point – on a standard lipid panel, it is this increased residence time and subsequent increase in TGRL that drives an increase in measured triglycerides. Recall that VLDL in cases of optimal metabolic health have a very short lifespan. When triglycerides are not liberated and this lifespan increases, total triglyceride count in the bloodstream increases. On lipid panels that include a VLDL-Cholesterol measurement, this increased lifespan can also be seen as an increase in VLDL-C, for the exact same reasons.

Distribution of Excess Triglycerides

But what happens to a VLDL when it can’t offload its triglycerides? In fact, it still does get rid of them. Only now they aren’t dropped off with fat and muscle cells, but instead transferred to other lipoproteins that must then share the burden of excess triglycerides. This is accomplished using a protein called cholesteryl-ester transfer protein (CETP), which mediates a cholesterol-for-triglyceride trade between VLDL and one of two potential trade partners.

The first of these trade partners is high-density lipoprotein (HDL), the “good” cholesterol measured on a standard lipid panel. Many people know they want their HDL to be high, but likely very few know that the main driver of depressed HDL is the action of CETP. When VLDL particles fail to sufficiently rid themselves of triglycerides, CETP helps trade some of them away to HDL. This process increases the cholesterol in the VLDL (also increasing measured VLDL-C), while decreasing the cholesterol in the HDL particle. Note that total cholesterol has not changed, only been rearranged. The same is true for total triglycerides. Now, instead of only the VLDL retaining excess triglycerides, the cholesterol-depleted HDL carry some as well.^10–12

The other potential trade partner is LDL. Remember, LDL are typically very poor in triglycerides. Following a CETP-mediated trade, LDL particles become slightly less rich in cholesterol and somewhat richer in triglycerides.^7,13 While this technically decreases the cholesterol in an LDL particle, it has effectively no impact on decreasing total LDL-cholesterol, as the VLDL particle that just took on that cholesterol may itself become an LDL particle within the hour.

Note now that the total triglyceride count has not been decreased, only redistributed. In healthy cases, when triglycerides are successfully liberated at the periphery, the VLDL are returned to the liver so that whatever triglycerides remain can be taken back up there. That remains true following CETP-mediated distribution of triglycerides following poor triglyceride uptake at the periphery, except now it is VLDL remnants, LDL, and HDL particles all returning to the liver to offload the excess triglycerides.

Excess Triglycerides Return to the Liver

There are two main effects of this increased triglyceride return. The first is obvious – more triglycerides are entering the liver, perhaps many more than is optimal. The second is the shrinking of the LDL and HDL particles that help traffic the triglycerides back to the liver. Remember, these particles have less cholesterol than they did previously, but their size before reaching the liver is unchanged thanks to the increase in triglycerides. After being freed of the triglycerides at the liver, however, these particles are now smaller than they were before the CETP-driven trade. The implications of this particle shrinking will be explored later.

It is the first effect we will continue focusing on now, however. Recall that at the end of the previous section, we posited that one of the ways by which VLDL production may be increased is by the presence of excess triglycerides in the liver.^14–17 Well, this process – the poor peripheral utilization and increased return of triglycerides to the liver – is arguably the most important factor propagating such an excess.

There are other factors too, however, and they very often occur in concert with the poor triglyceride uptake described in the preceding paragraphs. One is excess carbohydrate consumption, which not only decreases triglyceride utilization by raising blood sugar, but also increases de novo lipogenesis, the conversion of glucose to triglycerides that occurs in the liver following excess carbohydrate consumption.^14,15,17,18 An additional potential influence is increased body fat and insulin resistance. Typically, it is the action of insulin that prevents the breakdown of one’s own body fat. However, insulin resistance dulls this effect and allows this breakdown to occur even when the fatty acids being freed aren’t presently needed for energy production.^19,20 These free fatty acids travel on transport proteins back to the liver where they, too, are repackaged as triglycerides.

These factors combine to increase triglycerides in the liver to an unsustainable level (you may have heard of non-alcoholic fatty liver disease, which may result if this continues for too long). As a result, the production of triglyceride-rich VLDL must be increased in order to compensate. The production of these VLDL particles can be considered to be inappropriate, in that it is a response to metabolic dysfunction rather than to meet an actual need for the transport of triglycerides or cholesterol. Importantly, the failure to liberate triglycerides at the periphery will always be a persistent problem when this is the case. While excess carbohydrate consumption, body fat, and insulin resistance may continue to contribute, the effect of poor triglyceride utilization now spirals. Excess triglyceride production begets poor uptake, leading to increased return at the liver, greater excess production, and so forth.

All the while, HDL-C is decreased and HDL and LDL particles become smaller. As production continues to increase, excess VLDL particles, containing both triglycerides and cholesterol, inevitably become excess LDL particles. Even with a prolonged VLDL lifespan, the excess LDL exist multiple days longer and carry with them the cholesterol originally present in the VLDL. Thus, downstream from poor triglyceride utilization and increased return of triglycerides to the liver, LDL-cholesterol is increased.

**Key Takeaways:

• Insulin resistance and excess blood sugar decrease uptake of triglycerides by fat and muscle cells
• When triglyceride-carrying VLDL cannot offload triglycerides as efficiently, they exist for longer than is typical
• Prolonged VLDL lifespan is remedied by the CETP-mediated transfer of triglycerides to HDL and LDL particles, which decreases HDL-C
• Poor triglyceride uptake at the periphery causes increased triglyceride return to the liver, which helps contribute to an increased production of triglyceride-containing VLDL
• An increase in VLDL production in the metabolically unhealthy person leads to a subsequent increase in LDL particles and LDL-C

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

 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.           Wiczer B, Lobo S, Bernlohr D. Transport of fatty acids into adipocytes. Future Lipidology. 2006;1(3):291-298. doi:10.2217/17460875.1.3.291

5.           Lobo S, Bernlohr DA. Fatty acid transport in adipocytes and the development of insulin resistance. Fatty Acids and Lipotoxicity in Obesity and Diabetes. Published online 2007:113-121.

6.           Kovár J, Fejfarová V, Pelikánová T, Poledne R. Hyperglycemia Downregulates Total Lipoprotein Lipase Activity in Humans. Physiological research / Academia Scientiarum Bohemoslovaca. 2004;53:61-68. doi:10.33549/physiolres.930424

7.           Adiels M, Olofsson SO, Taskinen MR, Borén J. Overproduction of Very Low–Density Lipoproteins Is the Hallmark of the Dyslipidemia in the Metabolic Syndrome. Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28(7):1225-1236. doi:10.1161/ATVBAHA.107.160192

8.           Chan DC, Barrett PHR, Watts GF. Lipoprotein Kinetics in the Metabolic Syndrome: Pathophysiological and Therapeutic Lessons from Stable Isotope Studies. Clin Biochem Rev. 2004;25(1):31-48.

9.           Chan DC, Watts GF, Redgrave TG, Mori TA, Barrett PHR. Apolipoprotein B-100 kinetics in visceral obesity: Associations with plasma apolipoprotein C-III concentration. Metabolism. 2002;51(8):1041-1046. doi:10.1053/meta.2002.33339

10.         Hopkins GJ, Barter PJ. Role of triglyceride-rich lipoproteins and hepatic lipase in determining the particle size and composition of high density lipoproteins. Journal of Lipid Research. 1990;27(12):1265-1277. doi:10.1016/S0022-2275(20)38740-X

11.         Karpe F, Tornvall P, Olivecrona T, Steiner G, arlson LA, Hamsten A. Composition of human low density lipoprotein: Effects of postprandial triglyceride-rich lipoproteins, lipoprotein lipase, hepatic lipase and cholesteryl ester transfer protein. Atherosclerosis. 1993;98(1):33-49. doi:10.1016/0021-9150(93)90221-F

12.         Marcel YL, Vezina C, Teng B, Sniderman A. Transfer of cholesterol esters between human high density lipoproteins and triglyceride-rich lipoproteins controlled by a plasma protein factor. Atherosclerosis. 1980;35(2):127-133. doi:10.1016/0021-9150(80)90078-7

13.         Taskinen MR. Diabetic dyslipidaemia: from basic research to clinical practice*. Diabetologia. 2003;46(6):733-749. doi:10.1007/s00125-003-1111-y

14.         Flannery C, Dufour S, Rabøl R, Shulman GI, Petersen KF. Skeletal Muscle Insulin Resistance Promotes Increased Hepatic De Novo Lipogenesis, Hyperlipidemia, and Hepatic Steatosis in the Elderly. Diabetes. 2012;61(11):2711-2717. doi:10.2337/db12-0206

15.         Smith GI, Shankaran M, Yoshino M, et al. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J Clin Invest. 2020;130(3):1453-1460. doi:10.1172/JCI134165

16.         Lambert JE, Ramos–Roman MA, Browning JD, Parks EJ. Increased De Novo Lipogenesis Is a Distinct Characteristic of Individuals With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2014;146(3):726-735. doi:10.1053/j.gastro.2013.11.049

17.         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

18.         Hellerstein MK, Schwarz JM, Neese RA. Regulation of hepatic de novo lipogenesis in humans. Annu Rev Nutr. 1996;16:523-557. doi:10.1146/annurev.nu.16.070196.002515

19.         Tamura S, Shimomura I. Contribution of adipose tissue and de novo lipogenesis to nonalcoholic fatty liver disease. J Clin Invest. 2005;115(5):1139-1142. doi:10.1172/JCI24930

20.         Choi SM, Tucker DF, Gross DN, et al. Insulin Regulates Adipocyte Lipolysis via an Akt-Independent Signaling Pathway. Molecular and Cellular Biology. 2010;30(21):5009-5020. doi:10.1128/MCB.00797-10