ApoCIII

Apolipoprotein C-III (ApoCIII) is a small exchangeable apolipoprotein that circulates on triglyceride-rich lipoproteins such as chylomicrons and VLDL, with lesser presence on HDL. The APOC3 gene on chromosome 11 encodes the protein, which is chiefly synthesized by the liver and, to a lesser extent, the intestine.

ApoCIII modulates triglyceride metabolism by inhibiting lipoprotein lipase (LPL) and by impairing hepatic uptake of triglyceride-rich particles, thereby elevating plasma triglyceride levels. Its expression is influenced by nutrition, insulin signaling, and inflammatory states, and genetic variation can alter ApoCIII abundance and activity.

Genetic variants in APOC3 include loss-of-function mutations associated with lower triglyceride levels and reduced risk of coronary disease, illustrating ApoCIII’s causal role in triglyceride regulation. Elevated ApoCIII is linked to hypertriglyceridemia and pancreatitis when triglycerides are high.

Therapeutically, lowering ApoCIII has been pursued to reduce triglycerides. Antisense oligonucleotides targeting APOC3 (for example, volanesorsen) can substantially decrease triglycerides in severe hypertriglyceridemia, particularly familial chylomicronemia syndrome, but safety concerns such as thrombocytopenia have limited widespread use. Other RNA-based approaches are under investigation.