PURPOSE OF REVIEW: Apolipoprotein (apo) C-III is a key player in 
triglyceride-rich lipoprotein metabolism and strongly associated with elevated 
plasma triglyceride levels. Several new studies added important insights on 
apoC-III and its physiological function confirming its promise as a valid 
therapeutic target.
RECENT FINDINGS: APOC3 is expressed in liver and intestine and regulates 
triglyceride-rich lipoprotein (TRL) catabolism and anabolism. The 
transcriptional regulation in both organs requires different regulatory 
elements. Clinical and preclinical studies established that apoC-III raises 
plasma triglyceride levels predominantly by inhibiting hepatic TRL clearance. 
Mechanistic insights into missense variants indicate accelerated renal clearance 
of apoC-III variants resulting in enhanced TRL catabolism. In contrast, an APOC3 
gain-of-function variant enhances de novo lipogenesis and hepatic TRL 
production. Multiple studies confirmed the correlation between increased 
apoC-III levels and cardiovascular disease. This has opened up new therapeutic 
avenues allowing targeting of specific apoC-III properties in triglyceride 
metabolism.
SUMMARY: Novel in vivo models and APOC3 missense variants revealed unique 
mechanisms by which apoC-III inhibits TRL catabolism. Clinical trials with 
Volanesorsen, an APOC3 antisense oligonucleotide, report very promising 
lipid-lowering outcomes. However, future studies will need to address if acute 
apoC-III lowering will have the same clinical benefits as a life-long reduction.