APOC3 (apolipoprotein C3; HGNC:610, NCBI Gene ID 345) is a human locus mapped to chromosome band 11q23.3 that encodes apolipoprotein C-III secreted O-glycosylated peptide (79 mature aa). APOC3 acts in inhibition of lipoprotein lipase (LPL) & hepatic TRL remnant receptor uptake, together with LPL (Lipoprotein Lipase Gene), APOA5 (Apolipoprotein A-V Gene), and APOA1 (Apolipoprotein A-I Gene). Encodes apolipoprotein C-III, a potent inhibitor of plasma triglyceride clearance and validated target of ASO and siRNA therapeutics.
Genomic Organization & Cytogenetic Locus: 4-exon gene located within the APOA1-APOC3-APOA4-APOA5 gene cluster on chromosome 11q23.3, transcriptionally repressed by insulin-FOXO1 and PPAR-alpha and activated by glucose/ChREBP and HNF4alpha.
Cellular & Tissue Expression Profile: Synthesized predominantly in hepatic hepatocytes and to a lesser extent in small intestinal enterocytes, circulating on the surface of VLDL, chylomicrons, remnant lipoproteins, and HDL particles.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Elevates plasma triglycerides through two complementary mechanisms: at the capillary endothelium it displaces apolipoprotein C-II and inhibits lipoprotein lipase (LPL)-mediated lipolysis of triglyceride-rich lipoproteins, and at the hepatocyte space of Disse (Importantly, even in complete LPL deficiency) it blocks APOE- and APOB-mediated clearance of triglyceride-rich lipoprotein remnants via LDLR and LRP1.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Amish and population-wide carriers of heterozygous loss-of-function mutations (p.Arg19Ter, IVS2+1G>A, p.Ala43Thr) have ~40% lower plasma APOC3 and triglyceride levels, reduced postprandial lipemia, reduced coronary artery calcification, and a 40% lower risk of ischemic cardiovascular events.
Therapeutic & Clinical Pharmacology: Clinically validated target of RNA-targeted therapeutics: volanesorsen (Waylivra) and the GalNAc-conjugated antisense oligonucleotide olezarsen (Tryngolza, FDA-approved for familial chylomicronemia syndrome) as well as the GalNAc-siRNA plozasiran reduce plasma triglycerides by 50–80%.