Apolipoprotein C-III: Risk-factor, Regulator of Triglyceride-rich Lipoprotein Metabolism and Therapeutic Target

Apolipoprotein C-III (apoC-III) has emerged as a pivotal regulator of triglyceride metabolism and a key factor in cardiovascular risk. This review explores the physiological and pathological roles of apoC-III, focusing on kinetic mechanisms, genetic data, and the therapeutic potential of targeting apoC-III. Loss-of-function mutations in APOC3 significantly lower plasma triglyceride levels and coronary heart disease risk, validating apoC-III as a therapeutic target. Kinetic studies indicate that increased hepatic secretion of apoC-III raises triglyceride levels, particularly in individuals with type 2 diabetes. Beyond lipid metabolism, apoC-III promotes lipoprotein retention and amplifies arterial inflammation. Novel inhibitors, such as antisense oligonucleotides targeting APOC3, have been shown to markedly reduce plasma apoC-III and triglyceride concentrations in both preclinical and clinical studies. Genetic and mechanistic evidence together establish the inhibition of apoC-III as a promising strategy for patients at high risk of persistent hypertriglyceridemia and cardiovascular disease. ApoC-III not only controls lipid metabolism but also exerts direct pro-atherogenic and pro-inflammatory effects, supporting its role as a multifaceted therapeutic target in cardiometabolic medicine.