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).

Lowering apolipoprotein CIII protects against high-fat diet–induced metabolic derangements

“…6 ). A decrease in circulating Tgs and remnant cholesterol particles, less accumulation of atherogenic lipoproteins in the artery wall, and reduced endothelial inflammation result in a diminished risk for CVD ( 37 ).…”

Apolipoprotein CIII Is an Important Piece in the Type-1 Diabetes Jigsaw Puzzle

“…Under physiological conditions, apoCIII gene expression is negatively regulated by insulin, which represses the activity of the apoCIII promoter activity via inhibition of the insulin/phorbol ester responsive element (IRE) within the apoCIII gene [ 42 , 43 , 44 ]. The inhibitory action of insulin on the gene expression is mediated by the nuclear transcription factor forkhead box O1 (Foxo1), known as signal transductor of insulin for liver gluconeogenesis [ 38 , 45 , 46 ].…”

Large-Scale Analysis of Apolipoprotein CIII Glycosylation by Ultrahigh Resolution Mass Spectrometry

“…Apo-CIII is a novel potential drug target in the management of cardiovascular disease driven by multiple studies demonstrating that plasma levels of apo-CIII are predictive of coronary heart disease and the risk of disease-related events (Borén et al, 2020). Previously, it has been shown that sialylated apo-CIII glycoforms are differentially cleared by hepatic receptors and that a higher apo-CIII 2 /apo-CIII 1 ratio is associated with improved triglyceride levels (Kegulian et al, 2019).…”