Why Is Apolipoprotein CIII Emerging as a Novel Therapeutic Target to Reduce the Burden of Cardiovascular Disease?

Abstract

ApoC-III was discovered almost 50 years ago, but for many years, it did not attract much attention. However, as epidemiological and Mendelian randomization studies have associated apoC-III with low levels of triglycerides and decreased incidence of cardiovascular disease (CVD), it has emerged as a novel and potentially powerful therapeutic approach to managing dyslipidemia and CVD risk. The atherogenicity of apoC-III has been attributed to both direct lipoprotein lipase-mediated mechanisms and indirect mechanisms, such as promoting secretion of triglyceride-rich lipoproteins (TRLs), provoking proinflammatory responses in vascular cells and impairing LPL-independent hepatic clearance of TRL remnants. Encouraging results from clinical trials using antisense oligonucleotide, which selectively inhibits apoC-III, indicate that modulating apoC-III may be a potent therapeutic approach to managing dyslipidemia and cardiovascular disease risk.

Liraglutide treatment improves postprandial lipid metabolism and cardiometabolic risk factors in humans with adequately controlled type 2 diabetes: A single‐centre randomized controlled study

“…We also studied the impact of liraglutide on apoCIII, a critical regulator of postprandial triglyceride metabolism. Fasting apoCIII concentrations decreased markedly, by 10.7%, in the liraglutide group ( P = 0.018), but not in the placebo group ( P = 0.578).…”

“…Hepatic apoCIII expression is increased by glucose through activation of the carbohydrate‐responsive element‐binding protein (ChREBP). Therefore, apoCIII has been identified as an important link between hyperglycaemia and hypertriglyceridaemia . We recently demonstrated that both apoCIII and plasma triglycerides were markedly reduced by a carbohydrate‐restricted diet in obese patients with NAFLD .…”

Role of apolipoprotein C‐III overproduction in diabetic dyslipidaemia

“…In the circulation, apoC‐III is continuously exchanged between different lipoprotein particles and significant amounts of apoC‐III are carried not only on VLDL but also on low‐ and high‐density lipoprotein (LDL and HDL) particles . The distribution of apoC‐III among different lipoprotein fractions is dependent on the metabolic state, varying between the fasting and postprandial states and between subjects with normal and high plasma triglyceride levels . The impact of apoC‐III on CVD risk is complex but, in general, lipoproteins with high apoC‐III seem to be highly atherogenic …”

“…ApoC‐III has multiple actions on lipid metabolism as well as on proinflammatory and atherogenic processes . It is well known as an inhibitor of lipoprotein lipase (LPL), the rate‐limiting enzyme in the lipolytic process, and more recent data indicate that it also impairs the uptake of lipoprotein remnants by the liver .…”

“…Promoter analysis of APOC3 identified binding sites for transcription factors including the carbohydrate response element binding protein (ChREBP), which led to the proposal that glucose and plasma triglyceride metabolism are linked via the regulation of APOC3 expression . APOC3 expression is upregulated by glucose and downregulated by insulin, and it has been suggested that the glucose‐mediated expression of APOC3 may contribute to lower lipolysis and to an increase in peripheral glucose handling .…”