The Roles of ApoC-III on the Metabolism of Triglyceride-Rich Lipoproteins in Humans

Abstract

Cardiovascular disease (CVD) is the leading cause of death globally. It is well-established based on evidence accrued during the last three decades that high plasma concentrations of cholesterol-rich atherogenic lipoproteins are causatively linked to CVD, and that lowering these reduces atherosclerotic cardiovascular events in humans (1-9). Historically, most attention has been on low-density lipoproteins (LDL) since these are the most abundant atherogenic lipoproteins in the circulation, and thus the main carrier of cholesterol into the artery wall. However, with the rise of obesity and insulin resistance in many populations, there is increasing interest in the role of triglyceride-rich lipoproteins (TRLs) and their metabolic remnants, with accumulating evidence showing they too are causatively linked to CVD. Plasma triglyceride, measured either in the fasting or non-fasting state, is a useful index of the abundance of TRLs and recent research into the biology and genetics of triglyceride heritability has provided new insight into the causal relationship of TRLs with CVD. Of the genetic factors known to influence plasma triglyceride levels variation in APOC3- the gene for apolipoprotein (apo) C-III - has emerged as being particularly important as a regulator of triglyceride transport and a novel therapeutic target to reduce dyslipidaemia and CVD risk (10).

Keywords: apoC-III; cardiovascular disease; lipids; lipoproteins; triglycerides.

Figure 1

ApoC-III is an important mediator of an atherogenic dyslipidaemia and increased CVD risk. The hepatic APOC3 expression is induced by carbohydrates (glucose and fructose) and saturated fatty acid (SFA), and reduced by insulin and insulin and polyunsaturated fatty acid (PUFA) (18, 19, 31). Pharmacological intervention by FXR (28, 32, 33) and PPAR (, –36) agonists and APOC3 antisense oligonucleotides (ASO) reduces hepatic APOC3 expression (19). Statins (–39), niacin (40), and ezetimide (40) have been shown to lower plasma apoC-III levels. Increased apoC-III levels induce increase plasma levels of triglycerides and remnant cholesterol, and increased CVD risk. The mechanisms involve impaired lipolysis of TRLs and impaired hepatic clearance of TRL remnants. ApoC-III also facilitates subendothelial accumulation of atherogenic lipoproteins in the artery wall by increasing affinity of atherogenic lipoproteins to artery wall proteoglycans, promoting proinflammatory responses and increasing susceptibility to thrombotic events.