Biology:Apolipoprotein C-III
 Generic protein structure example |
Apolipoprotein C-III also known as apo-CIII, and apolipoprotein C3, 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 | |||||||||
| Symbol | ApoC-III | ||||||||
| Pfam | PF05778 | ||||||||
| InterPro | IPR008403 | ||||||||
| |||||||||
ApoC-III 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
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
- ↑ 1.0 1.1 "A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels". Nature Medicine 23 (9): 1086–1094. 2017. doi:10.1038/nm.4390. PMID 28825717.
- ↑ "Characterization of the oligosaccharide side chain of apolipoprotein C-III from human plasma very low density lipoproteins". Biochimica et Biophysica Acta (BBA) - General Subjects 541 (2): 234–40. Jun 1978. doi:10.1016/0304-4165(78)90396-3. PMID 208636.
- ↑ "Identification of new apolipoprotein-CIII glycoforms with ultrahigh resolution MALDI-FTICR mass spectrometry of human sera". Journal of Proteome Research 12 (5): 2260–68. May 2013. doi:10.1021/pr400136p. PMID 23527852.
- ↑ "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. Feb 2010. doi:10.1161/ATVBAHA.109.197830. PMID 19910636.
- ↑ "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. Jan 2010. doi:10.1194/M900346-JLR200. PMID 19622837.
- ↑ "Functional analysis of the missense APOC3 mutation Ala23Thr associated with human hypotriglyceridemia". Journal of Lipid Research 51 (6): 1524–1534. Jun 2010. doi:10.1194/jlr.M005108. PMID 20097930.
- ↑ "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. Aug 2011. doi:10.1074/jbc.M110.203679. PMID 21676879.
- ↑ "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. Nov 2008. doi:10.1016/j.ijcard.2007.07.029. PMID 17825930.
- ↑ "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. Jun 2007. doi:10.3132/dvdr.2007.030. PMID 17654446.
- ↑ "Plasma apolipoprotein C-III levels, triglycerides, and coronary artery calcification in type 2 diabetics". Arteriosclerosis, Thrombosis, and Vascular Biology 35 (8): 1880–1888. 2015. doi:10.1161/ATVBAHA.115.305415. PMID 26069232.
- ↑ "Complexities of plasma apolipoprotein C-III metabolism". Journal of Lipid Research 52 (6): 1067–1070. 2011. doi:10.1194/jlr.E015701. PMID 21421846.
- ↑ "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 (39): 10491–10502. 2008. doi:10.1021/bi801249c. PMID 18767813.
External links
- Apolipoprotein+C-III at the US National Library of Medicine Medical Subject Headings (MeSH)
- Human APOC3 genome location and APOC3 gene details page in the UCSC Genome Browser.
Further reading
- "Apolipoprotein C-III(Lys58----Glu). Identification of an apolipoprotein C-III variant in a family with hyperalphalipoproteinemia". The Journal of Clinical Investigation 87 (5): 1724–31. May 1991. doi:10.1172/JCI115190. PMID 2022742.
- "Isolation and characterization of cDNA clones corresponding to two different human apoC-III alleles". Journal of Lipid Research 26 (4): 451–56. Apr 1985. doi:10.1016/S0022-2275(20)34359-5. PMID 2989400.
- "Structure, evolution, and polymorphisms of the human apolipoprotein A4 gene (APOA4)". Proceedings of the National Academy of Sciences of the United States of America 83 (22): 8457–61. Nov 1986. doi:10.1073/pnas.83.22.8457. PMID 3095836. Bibcode: 1986PNAS...83.8457K.
- "Molecular cloning of a human apoC-III variant: Thr 74----Ala 74 mutation prevents O-glycosylation". Journal of Lipid Research 28 (12): 1405–09. Dec 1987. doi:10.1016/S0022-2275(20)38574-6. PMID 3123586.
- "Apolipoprotein multigene family: tandem organization of human apolipoprotein AI, CIII, and AIV genes". Proceedings of the National Academy of Sciences of the United States of America 82 (19): 6374–78. Oct 1985. doi:10.1073/pnas.82.19.6374. PMID 3931073. Bibcode: 1985PNAS...82.6374K.
- "Distribution of apolipoprotein A-I, C-II, C-III, and E mRNA in fetal human tissues. Time-dependent induction of apolipoprotein E mRNA by cultures of human monocyte-macrophages". Biochemistry 24 (16): 4450–55. Jul 1985. doi:10.1021/bi00337a028. PMID 3931677.
- "Comparison of the human apolipoprotein genes. Apo AII presents a unique functional intron-exon junction". Journal of Molecular Biology 186 (1): 43–51. Nov 1985. doi:10.1016/0022-2836(85)90255-4. PMID 3935800.
- "Amino acid sequence of human plasma apolipoprotein C-III from normolipidemic subjects". FEBS Letters 197 (1–2): 67–73. Mar 1986. doi:10.1016/0014-5793(86)80300-3. PMID 3949020.
- "The complete amino acid sequence of alanine apolipoprotein (apoC-3), and apolipoprotein from human plasma very low density lipoproteins". The Journal of Biological Chemistry 249 (15): 4975–84. Aug 1974. doi:10.1016/S0021-9258(19)42416-2. PMID 4846755.
- "Linkage of human apolipoproteins A-I and C-III genes". Nature 304 (5924): 371–73. 1983. doi:10.1038/304371a0. PMID 6308458. Bibcode: 1983Natur.304..371K.
- "Human apolipoproteins AI, AII, CII and CIII. cDNA sequences and mRNA abundance". Nucleic Acids Research 12 (9): 3917–32. May 1984. doi:10.1093/nar/12.9.3917. PMID 6328445.
- "cDNA cloning of human apoA-I: amino acid sequence of preproapoA-I". Biochemical and Biophysical Research Communications 112 (1): 257–64. Apr 1983. doi:10.1016/0006-291X(83)91824-7. PMID 6404278.
- "Isolation and sequence analysis of the human apolipoprotein CIII gene and the intergenic region between the apo AI and apo CIII genes". DNA 3 (6): 449–56. Dec 1984. doi:10.1089/dna.1.1984.3.449. PMID 6439535.
- "Isolation and DNA sequence of full-length cDNA for human preapolipoprotein CIII". DNA 3 (5): 359–64. Oct 1984. doi:10.1089/dna.1984.3.359. PMID 6548954.
- "An apolipoprotein CIII haplotype protective against hypertriglyceridemia is specified by promoter and 3' untranslated region polymorphisms". Proceedings of the National Academy of Sciences of the United States of America 90 (10): 4562–66. May 1993. doi:10.1073/pnas.90.10.4562. PMID 8099442. Bibcode: 1993PNAS...90.4562D.
- "DNA polymorphisms at the apolipoprotein A1-CIII loci in Taiwanese: correlation of plasma APOCIII with triglyceride level and body mass index". Journal of the Formosan Medical Association = Taiwan Yi Zhi 99 (5): 367–74. May 2000. PMID 10870325.
- "Gene expression patterns in the lungs of patients with primary pulmonary hypertension: a gene microarray analysis". Circulation Research 88 (6): 555–62. Mar 2001. doi:10.1161/01.RES.88.6.555. PMID 11282888.
- "Reactivation of liver-specific gene expression in an immortalized human hepatocyte cell line by introduction of the human HNF4alpha2 gene". International Journal of Molecular Medicine 8 (5): 481–87. Nov 2001. doi:10.3892/ijmm.8.5.481. PMID 11605014.
- "Two initiator-like elements are required for the combined activation of the human apolipoprotein C-III promoter by upstream stimulatory factor and hepatic nuclear factor-4". The Journal of Biological Chemistry 277 (17): 15199–206. Apr 2002. doi:10.1074/jbc.M200227200. PMID 11839757.
- "Apolipoprotein C3 SstI polymorphism and triglyceride levels in Asian Indians". BMC Genetics 3: 9. Jun 2002. doi:10.1186/1471-2156-3-9. PMID 12052247.
 |
