Apolipoprotein C3

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

Apolipoprotein C-III also known as apo-CIII is a protein that in humans is encoded by the APOC3 gene. 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.,[1]

Structure

ApoC-III
Identifiers
SymbolApoC-III
PfamPF05778
InterProIPR008403

ApoCIII is a relatively small protein containing 79 amino acids that can be glycosylated at threonine-74.[2] The most abundant glycoforms are characterized by an O-linked disaccharide galactose linked to N-acetylgalactosamine (Gal- GalNAc), further modified with up to 2 sialic acid residues. Less abundant glycoforms are characterized by more complex and fucosylated glycan moieties.[3]

Function

APOC3 inhibits lipoprotein lipase and hepatic lipase; it is thought to inhibit hepatic uptake[4] 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 evidences suggest an intracellular role for Apo-CIII in promoting the assembly and secretion of triglyceride-rich VLDL particles from hepatic cells under lipid-rich conditions.[5] 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.[6][7]

Clinical significance

Overexpression of Apo-CIII in humans contributes to atherosclerosis.[1] 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[8] as well as non-insulin diabetes mellitus.[9] In persons with type 2 diabetes, elevated plasma Apo-CIII is associated with higher plasma triglycerides and greater coronary artery calcification (a measure of subclinical atherosclerosis).[10]

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.[11]

Elevations of Apo-CIII found in genetic variation studies may predispose patients to non-alcoholic fatty liver disease.

Interactive pathway map

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 and HDL

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.[12] 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.

References

  1. 1.0 1.1 Khetarpal SA, Zeng X, Millar JS, Vitali C, Somasundara AVH, Zanoni P, Landro JA, Barucci N, Zavadoski WJ, Sun Z, de Haard H, Toth IV, Peloso GM, Natarajan P, Cuchel M, Lund-Katz S, Phillips MC, Tall AR, Kathiresan S, DaSilva-Jardine P, Yates NA, Rader D (2017). "A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels". Nature Medicine. 23 (9): 1086–1094. doi:10.1038/nm.4390. PMC 5669375. PMID 28825717.
  2. Vaith P, Assmann G, Uhlenbruck G (Jun 1978). "Characterization of the oligosaccharide side chain of apolipoprotein C-III from human plasma very low density lipoproteins". Biochimica et Biophysica Acta. 541 (2): 234–40. doi:10.1016/0304-4165(78)90396-3. PMID 208636.
  3. Nicolardi S, van der Burgt YE, Dragan I, Hensbergen PJ, Deelder AM (May 2013). "Identification of new apolipoprotein-CIII glycoforms with ultrahigh resolution MALDI-FTICR mass spectrometry of human sera". Journal of Proteome Research. 12 (5): 2260–68. doi:10.1021/pr400136p. PMID 23527852.
  4. Mendivil CO, Zheng C, Furtado J, Lel J, Sacks FM (Feb 2010). "Metabolism of very-low-density lipoprotein and low-density lipoprotein containing apolipoprotein C-III and not other small apolipoproteins". Arteriosclerosis, Thrombosis, and Vascular Biology. 30 (2): 239–45. doi:10.1161/ATVBAHA.109.197830. PMC 2818784. PMID 19910636.
  5. Sundaram M, Zhong S, Bou Khalil M, Links PH, Zhao Y, Iqbal J, Hussain MM, Parks RJ, Wang Y, Yao Z (Jan 2010). "Expression of apolipoprotein C-III in McA-RH7777 cells enhances VLDL assembly and secretion under lipid-rich conditions". Journal of Lipid Research. 51 (1): 150–161. doi:10.1194/M900346-JLR200. PMC 2789775. PMID 19622837.
  6. Sundaram M, Zhong S, Bou Khalil M, Zhou H, Jiang ZG, Zhao Y, Iqbal J, Hussain MM, Figeys D, Wang Y, Yao Z (Jun 2010). "Functional analysis of the missense APOC3 mutation Ala23Thr associated with human hypotriglyceridemia". Journal of Lipid Research. 51 (6): 1524–1534. doi:10.1194/jlr.M005108. PMC 3035516. PMID 20097930.
  7. Qin W, Sundaram M, Wang Y, Zhou H, Zhong S, Chang CC, Manhas S, Yao EF, Parks RJ, McFie PJ, Stone SJ, Jiang ZG, Wang C, Figeys D, Jia W, Yao Z (Aug 2011). "Missense mutation in APOC3 within the C-terminal lipid binding domain of human ApoC-III results in impaired assembly and secretion of triacylglycerol-rich very low density lipoproteins: evidence that ApoC-III plays a major role in the formation of lipid precursors within the microsomal lumen". The Journal of Biological Chemistry. 286 (31): 27769–27780. doi:10.1074/jbc.M110.203679. PMC 3149367. PMID 21676879.
  8. Singh P, Singh M, Kaur TP, Grewal SS (Nov 2008). "A novel haplotype in ApoAI-CIII-AIV gene region is detrimental to Northwest Indians with coronary heart disease". International Journal of Cardiology. 130 (3): e93–5. doi:10.1016/j.ijcard.2007.07.029. PMID 17825930.
  9. Singh P, Singh M, Gaur S, Kaur T (Jun 2007). "The ApoAI-CIII-AIV gene cluster and its relation to lipid levels in type 2 diabetes mellitus and coronary heart disease: determination of a novel susceptible haplotype". Diabetes & Vascular Disease Research. 4 (2): 124–29. doi:10.3132/dvdr.2007.030. PMID 17654446.open access publication – free to read
  10. Qamar A, Khetarpal SA, Khera AV, Qasim A, Rader DJ, Reilly MP (2015). "Plasma apolipoprotein C-III levels, triglycerides, and coronary artery calcification in type 2 diabetics". Arteriosclerosis, Thrombosis, and Vascular Biology. 35 (8): 1880–1888. doi:10.1161/ATVBAHA.115.305415. PMC 4556282. PMID 26069232.
  11. Sacks FM, Zheng C, Cohn JS (2011). "Complexities of plasma apolipoprotein C-III metabolism". Journal of Lipid Research. 52 (6): 1067–1070. doi:10.1194/jlr.E015701. PMC 3090227. PMID 21421846.
  12. Kypreos KE (2008). "ABCA1 Promotes the de Novo Biogenesis of Apolipoprotein CIII-Containing HDL Particles in Vivo and Modulates the Severity of Apolipoprotein CIII-Induced Hypertriglyceridemia". Biochemistry. 47: 10491–10502. doi:10.1021/bi801249c.

External links

Further reading