Apolipoprotein C-III

Apolipoprotein C-III also known as apo-CIII, and apolipoprotein C3, is a protein that in humans is encoded by the APOC3gene. Apo-CIII is secreted by the liver as well as the small intestine, and is found on triglyceride-rich lipoproteins such as chylomicrons, very low density lipoprotein (VLDL), and remnant cholesterol.^[5]

ApoC-III is a relatively small protein containing 79 amino acids that can be glycosylated at threonine-74.^[6] The most abundant glycoforms are characterized by an O-linked disaccharide galactose linked to N-acetylgalactosamine (Gal–GalNAc), further modified with up to two sialic acid residues. Less abundant glycoforms are characterized by more complex and fucosylatedglycan moieties.^[7]

APOC3 inhibits lipoprotein lipase and hepatic lipase; it is thought to inhibit hepatic uptake^[8] of triglyceride-rich particles. The APOA1, APOC3 and APOA4 genes are closely linked in both rat and human genomes. The A-I and A-IV genes are transcribed from the same strand, while the A-1 and C-III genes are convergently transcribed. An increase in apoC-III levels induces the development of hypertriglyceridemia. Recent evidence suggests an intracellular role for Apo-CIII in promoting the assembly and secretion of triglyceride-rich VLDL particles from hepatic cells under lipid-rich conditions.^[9] However, two naturally occurring point mutations in human apoC3 coding sequence, namely Ala23Thr and Lys58Glu have been shown to abolish the intracellular assembly and secretion of triglyceride-rich VLDL particles from hepatic cells.^[10][11]

Overexpression of Apo-CIII in humans contributes to atherosclerosis.^[5] Two novel susceptibility haplotypes (specifically, P2-S2-X1 and P1-S2-X1) have been discovered in ApoAI-CIII-AIV gene cluster on chromosome 11q23; these confer approximately threefold higher risk of coronary heart disease in normal^[12] as well as non-insulin diabetes mellitus.^[13] In persons with type 2 diabetes, elevated plasma Apo-CIII is associated with higher plasma triglycerides and greater coronary arterycalcification (a measure of subclinical atherosclerosis).^[14]

Apo-CIII delays the catabolism of triglyceride rich particles. HDL cholesterol particles that bear Apo-CIII are associated with increased, rather than decreased, risk for coronary heart disease.^[15]

Elevations of Apo-CIII associated with single-nucleotide polymorphisms found in genetic variation studies may predispose patients to non-alcoholic fatty liver disease,^[16] although the association has been questioned^[17] and may be specific to certain ethnicities^[18][19] or to people without central obesity.^[20]

Antisense oligonucleotides that bind APOC3 mRNA and prevent its translation have been found to reduce episodes of acute pancreatitis in people with familial chylomicronemia syndrome and lower their triglyceride levels in blood. Adverse effects include thrombocytopenia, which may be prevented by targeting hepatocellularAPOC3 expression with a chemically modified oligonucleotide.^[21]

Click on genes, proteins and metabolites below to link to respective articles.^{[§ 1]}

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Statin pathway edit

1. ↑The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".

Apolipoprotein CIII is also found on HDL particles. Formation of APOCIII-containing HDL is not a matter of simple binding of APOCII to pre-existing HDL particles but requires the lipid transported ABCA1 in a fashion similar to APOA1-containing HDL.^[22] Accumulation of APOCIII on HDL is important for the maintenance of plasma triglyceride homeostasis since it prevents excessive amount of APOCIII on VLDL and other triglyceride rich lipoproteins, thus preventing APOCIII-mediated inhibition of LpL and the subsequent hydrolysis of plasma triglycerides. This may explain the hypertriglyceridemia associated with ABCA1-deficiency in patients with Tangier's disease.

• Apolipoprotein+C-III at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human APOC3 genome location and APOC3 gene details page in the UCSC Genome Browser.