What is the role of chylomicron and VLDL metabolism in the pathophysiology of hypertriglyceridemia (high triglyceride levels)?

Updated: Jul 23, 2021
  • Author: Mary Ellen T Sweeney, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
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Answer

Any disturbance that causes increased synthesis of chylomicrons and/or VLDLs or decreased metabolic breakdown causes elevations in triglyceride levels. That disturbance may be as common as dietary indiscretion or as unusual as a genetic mutation of an enzyme in the lipid metabolism pathway. Essentially, hypertriglyceridemia occurs through 1 of the following 3 processes [13] :

  • Abnormalities in hepatic VLDL production, and intestinal chylomicron synthesis

  • Dysfunctional lipoprotein lipase -mediated lipolysis

  • Impaired remnant clearance

As shown in the images below, chylomicrons and VLDLs are initially metabolized by lipoprotein lipase, which hydrolyzes the triglycerides, releasing FFAs; these FFAs are stored in fat and muscle. With normal lipoprotein lipase activity, the half-lives of chylomicrons and VLDLs are about 10 minutes and 9 hours, respectively. Because of the large size of unmetabolized chylomicrons, they are unlikely to be taken up by macrophages, which are the precursors of foam cells. Foam cells promote fatty streak formation, the precursor of atherosclerotic plaque. Lipoprotein lipase activity produces chylomicron remnants that are small enough to take part in the atherosclerotic process. Chylomicron remnants are taken up by the LDL receptor or the LDL receptor-related protein. [14]

Lipoprotein lipase (LPL) releases free fatty acids Lipoprotein lipase (LPL) releases free fatty acids (FFAs) from chylomicrons (chylo) and produces chylomicron remnants that are small enough to take part in the atherosclerotic process. Chol = cholesterol; TGs, TGS = triglycerides.
Once very low-density lipoprotein (VLDL) has been Once very low-density lipoprotein (VLDL) has been metabolized by lipoprotein lipase, VLDL remnants in the form of intermediate-density lipoprotein (IDL) can be metabolized by hepatic lipase, producing low-density lipoprotein (LDL), or they can be taken up by the LDL receptor via either apolipoprotein B (apo B) or apo E. Chol = cholesterol; TGs = triglycerides.

VLDL remnants have 1 of 2 fates: they can be metabolized by hepatic lipase, which further depletes triglycerides, producing LDL, or they can be taken up by the LDL receptor via either apo B or apo E. VLDL remnants are not only triglyceride-poor, they are also cholesterol enriched, having acquired cholesterol ester from HDL via the action of cholesterol ester transfer protein (CETP), which facilitates the exchange of VLDL triglycerides for cholesterol in HDL. This pathway may promote HDL's reverse cholesterol transport activity, but only if VLDL and LDL return cholesterol to the liver. If these lipoproteins are taken up by macrophages, the CETP transfer results in increased atherogenesis.

Chylomicron remnants, VLDL, VLDL remnants, and LDL are all atherogenic.


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