Apolipoprotein C3: Difference between revisions

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{{Infobox_gene}}
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'''Apolipoprotein C-III''' also known as '''apo-CIII''' is a [[protein]] that in humans is encoded by the APOC3 [[gene]]. Apo-CIII is a component of [[very low density lipoprotein]] (VLDL).
| require_manual_inspection = no
 
| update_protein_box = yes
== Structure ==
| update_summary = no
{{Infobox protein family
| update_citations = yes
| align = left
| Symbol = ApoC-III
| Name = ApoC-III
| image =
| width =
| caption = structure and dynamics of human apolipoprotein c-iii
| Pfam = PF05778
| Pfam_clan = 
| InterPro = IPR008403
| SMART =
| PROSITE =
| MEROPS =
| SCOP =
| TCDB =  
| OPM family =  
| OPM protein =  
| CAZy =  
| CDD =  
}}
}}
ApoCIII is a relatively small protein containing 79 amino acids that can be [[glycosylated]] at [[threonine]]-74.<ref name="pmid208636">{{cite journal | vauthors = Vaith P, Assmann G, Uhlenbruck G | title = Characterization of the oligosaccharide side chain of apolipoprotein C-III from human plasma very low density lipoproteins | journal = Biochimica et Biophysica Acta | volume = 541 | issue = 2 | pages = 234–40 | date = Jun 1978 | pmid = 208636 | doi = 10.1016/0304-4165(78)90396-3 }}</ref> 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 [[fucosylation|fucosylated]] [[glycan]] moieties.<ref name="pmid23527852">{{cite journal | vauthors = Nicolardi S, van der Burgt YE, Dragan I, Hensbergen PJ, Deelder AM | title = Identification of new apolipoprotein-CIII glycoforms with ultrahigh resolution MALDI-FTICR mass spectrometry of human sera | journal = Journal of Proteome Research | volume = 12 | issue = 5 | pages = 2260–68 | date = May 2013 | pmid = 23527852 | doi = 10.1021/pr400136p }}</ref>
{{clear|left}}
== Function ==
APOC3 inhibits [[lipoprotein lipase]] and [[hepatic lipase]]; it is thought to inhibit hepatic uptake<ref>{{cite journal | vauthors = Mendivil CO, Zheng C, Furtado J, Lel J, Sacks FM | title = Metabolism of very-low-density lipoprotein and low-density lipoprotein containing apolipoprotein C-III and not other small apolipoproteins | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 30 | issue = 2 | pages = 239–45 | date = Feb 2010 | pmid = 19910636 | pmc = 2818784 | doi = 10.1161/ATVBAHA.109.197830 }}</ref> of [[triglyceride]]-rich particles. The [[APOA1]], APOC3 and [[APOA4]] genes are closely linked in both rat and human [[genome]]s. 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.<ref>{{cite journal | vauthors = Sundaram M, Zhong S, Bou Khalil M, Links PH, Zhao Y, Iqbal J, Hussain MM, Parks RJ, Wang Y, Yao Z | title = Expression of apolipoprotein C-III in McA-RH7777 cells enhances VLDL assembly and secretion under lipid-rich conditions | journal = Journal of Lipid Research | volume = 51 | issue = 1 | pages = 150–161 | date = Jan 2010 | pmid = 19622837 | doi = 10.1194/M900346-JLR200 | pmc=2789775}}</ref> 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.<ref>{{cite journal | vauthors = Sundaram M, Zhong S, Bou Khalil M, Zhou H, Jiang ZG, Zhao Y, Iqbal J, Hussain MM, Figeys D, Wang Y, Yao Z | title = Functional analysis of the missense APOC3 mutation Ala23Thr associated with human hypotriglyceridemia | journal = Journal of Lipid Research | volume = 51 | issue = 6 | pages = 1524–1534 | date = Jun 2010 | pmid = 20097930 | doi = 10.1194/jlr.M005108 | pmc=3035516}}</ref><ref>{{cite journal | vauthors = 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 | title = 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 | journal = The Journal of Biological Chemistry | volume = 286 | issue = 31 | pages = 27769–27780 | date = Aug 2011 | pmid = 21676879 | doi = 10.1074/jbc.M110.203679 | pmc=3149367}}</ref>
== Clinical significance ==
Two novel susceptibility [[haplotypes]] (specifically, P2-S2-X1 and P1-S2-X1) have been discovered in ApoAI-CIII-AIV [[gene cluster]] on [[chromosome 11]]q23; these confer approximately threefold higher risk of [[coronary heart disease]] in normal<ref>{{cite journal | vauthors = Singh P, Singh M, Kaur TP, Grewal SS | title = A novel haplotype in ApoAI-CIII-AIV gene region is detrimental to Northwest Indians with coronary heart disease | journal = International Journal of Cardiology | volume = 130 | issue = 3 | pages = e93–5 | date = Nov 2008 | pmid = 17825930 | doi = 10.1016/j.ijcard.2007.07.029 }}</ref> as well as [[Diabetes mellitus type 2|non-insulin diabetes mellitus]].<ref>{{cite journal | vauthors = Singh P, Singh M, Gaur S, Kaur T | title = 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 | journal = Diabetes & Vascular Disease Research | volume = 4 | issue = 2 | pages = 124–29 | date = Jun 2007 | pmid = 17654446 | doi = 10.3132/dvdr.2007.030 }}</ref>  In persons with [[Diabetes mellitus type 2|type 2 diabetes]], elevated plasma Apo-CIII is associated with higher plasma [[triglyceride]]s and greater [[Coronary circulation|coronary artery]] [[calcification]] (a measure of subclinical [[atherosclerosis]]).<ref name="pmid26069232 ">{{cite journal | vauthors=Qamar A, Khetarpal SA, Khera AV, Qasim A, Rader DJ, Reilly MP | title=Plasma apolipoprotein C-III levels, triglycerides, and coronary artery calcification in type 2 diabetics | journal= [[Arteriosclerosis, Thrombosis, and Vascular Biology]] | volume=35 | issue=8 | pages=1880–1888 | year=2015 | doi= 10.1161/ATVBAHA.115.305415 |url=http://atvb.ahajournals.org/content/35/8/1880.long  | PMC=4556282 | PMID = 26069232  }}</ref>
Apo-CIII delays the catabolism of triglyceride rich particles. [[High-density lipoprotein|HDL cholesterol]] particles that bear Apo-CIII are associated with increased, rather than decreased, risk for coronary heart disease.<ref name="pmid21421846">{{cite journal | vauthors=Sacks FM, Zheng C, Cohn JS | title=Complexities of plasma apolipoprotein C-III metabolism | journal= [[Journal of Lipid Research]] | volume=52 | issue=6 | pages=1067–1070 | year=2011 | doi= 10.1194/jlr.E015701 |url=http://www.jlr.org/content/52/6/1067.long | PMC=3090227 | PMID = 21421846}}</ref>
Elevations of Apo-CIII found in genetic variation studies may predispose patients to non-alcoholic fatty liver disease.
==Interactive pathway map==
{{StatinPathway_WP430|highlight=Apolipoprotein_C3}}


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==Apolipoprotein CIII and HDL==
{{GNF_Protein_box
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.<ref>{{cite journal | vauthors = Kypreos KE | year = 2008 | title = ABCA1 Promotes the de Novo Biogenesis of Apolipoprotein CIII-Containing HDL Particles in Vivo and Modulates the Severity of Apolipoprotein CIII-Induced Hypertriglyceridemia | url = | journal = Biochemistry | volume = 47 | issue = | pages = 10491–10502 | doi=10.1021/bi801249c}}</ref> Interestingly, 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.
| image =
| image_source =
| PDB =
| Name = Apolipoprotein C-III
| HGNCid = 610
| Symbol = APOC3
| AltSymbols =; APOCIII; MGC150353
| OMIM = 107720
| ECnumber =
| Homologene = 81615
| MGIid = 88055
| GeneAtlas_image1 = PBB_GE_APOC3_205820_s_at_tn.png
| Function = {{GNF_GO|id=GO:0005319 |text = lipid transporter activity}} {{GNF_GO|id=GO:0008289 |text = lipid binding}}
| Component = {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0042627 |text = chylomicron}}
| Process = {{GNF_GO|id=GO:0006641 |text = triacylglycerol metabolic process}} {{GNF_GO|id=GO:0006869 |text = lipid transport}} {{GNF_GO|id=GO:0016042 |text = lipid catabolic process}} {{GNF_GO|id=GO:0042157 |text = lipoprotein metabolic process}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 345
    | Hs_Ensembl = ENSG00000110245
    | Hs_RefseqProtein = NP_000031
    | Hs_RefseqmRNA = NM_000040
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 11
    | Hs_GenLoc_start = 116205818
    | Hs_GenLoc_end = 116208998
    | Hs_Uniprot = P02656
    | Mm_EntrezGene = 11814
    | Mm_Ensembl = ENSMUSG00000032081
    | Mm_RefseqmRNA = NM_023114
    | Mm_RefseqProtein = NP_075603
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 9
    | Mm_GenLoc_start = 45984046
    | Mm_GenLoc_end = 45986292
    | Mm_Uniprot = P33622
  }}
}}
'''Apolipoprotein C-III''' is a very low density lipoprotein (VLDL) protein. APOC3 inhibits [[lipoprotein lipase]] and [[hepatic lipase]]; it is thought to delay catabolism 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]].


==See also==
== References ==
* [[Apolipoprotein]]
{{reflist|35em}}
Lately, two novel susceptibility haplotypes i.e. P2-S2-X1 and P1-S2-X1 have been discovered in ApoAI-CIII-AIV gene cluster on chromosme 11q23, who confer approximately threefold higher risk of coronary heart disease in normal [http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17825930&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum] as well as non-insulin diabetes mellitus[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17654446&ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum].


==External links==
== External links ==
* {{MeshName|Apolipoprotein+C-III}}
* {{MeshName|Apolipoprotein+C-III}}
* {{UCSC gene info|APOC3}}
{{Clear}}


==References==
== Further reading ==
{{reflist|2}}
{{refbegin|35em}}
 
* {{cite journal | vauthors = von Eckardstein A, Holz H, Sandkamp M, Weng W, Funke H, Assmann G | title = Apolipoprotein C-III(Lys58----Glu). Identification of an apolipoprotein C-III variant in a family with hyperalphalipoproteinemia | journal = The Journal of Clinical Investigation | volume = 87 | issue = 5 | pages = 1724–31 | date = May 1991 | pmid = 2022742 | pmc = 295277 | doi = 10.1172/JCI115190 }}
==Further reading==
* {{cite journal | vauthors = Karathanasis SK, Zannis VI, Breslow JL | title = Isolation and characterization of cDNA clones corresponding to two different human apoC-III alleles | journal = Journal of Lipid Research | volume = 26 | issue = 4 | pages = 451–56 | date = Apr 1985 | pmid = 2989400 }}
{{refbegin | 2}}
* {{cite journal | vauthors = Karathanasis SK, Oettgen P, Haddad IA, Antonarakis SE | title = Structure, evolution, and polymorphisms of the human apolipoprotein A4 gene (APOA4) | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 22 | pages = 8457–61 | date = Nov 1986 | pmid = 3095836 | pmc = 386949 | doi = 10.1073/pnas.83.22.8457 }}
{{PBB_Further_reading
* {{cite journal | vauthors = Maeda H, Hashimoto RK, Ogura T, Hiraga S, Uzawa H | title = Molecular cloning of a human apoC-III variant: Thr 74----Ala 74 mutation prevents O-glycosylation | journal = Journal of Lipid Research | volume = 28 | issue = 12 | pages = 1405–09 | date = Dec 1987 | pmid = 3123586 }}
| citations =
* {{cite journal | vauthors = Karathanasis SK | title = Apolipoprotein multigene family: tandem organization of human apolipoprotein AI, CIII, and AIV genes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 19 | pages = 6374–78 | date = Oct 1985 | pmid = 3931073 | pmc = 390718 | doi = 10.1073/pnas.82.19.6374 }}
*{{cite journal | author=Singh PP, Singh M, Kaur TP, Grewal SS|title=A novel haplotype in ApoAI-CIII-AIV gene region is detrimental to Northwest Indians with coronary heart disease |journal= Int J Cardiol |year= 2007 |pmid= 17825930 |doi= }}
* {{cite journal | vauthors = Zannis VI, Cole FS, Jackson CL, Kurnit DM, Karathanasis SK | title = 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 | journal = Biochemistry | volume = 24 | issue = 16 | pages = 4450–55 | date = Jul 1985 | pmid = 3931677 | doi = 10.1021/bi00337a028 }}
*{{cite journal | author=Singh PP, Singh M, Gaur S, Grewal SS|title=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.|journal= Diab Vasc Dis Res |volume=4 |issue= 2 |pages= 124-29 |year= 2007 |pmid= 17654446 |doi=  }}
* {{cite journal | vauthors = Shelley CS, Sharpe CR, Baralle FE, Shoulders CC | title = Comparison of the human apolipoprotein genes. Apo AII presents a unique functional intron-exon junction | journal = Journal of Molecular Biology | volume = 186 | issue = 1 | pages = 43–51 | date = Nov 1985 | pmid = 3935800 | doi = 10.1016/0022-2836(85)90255-4 }}
*{{cite journal | author=von Eckardstein A, Holz H, Sandkamp M, ''et al.'' |title=Apolipoprotein C-III(Lys58----Glu). Identification of an apolipoprotein C-III variant in a family with hyperalphalipoproteinemia. |journal=J. Clin. Invest. |volume=87 |issue= 5 |pages= 1724-31 |year= 1991 |pmid= 2022742 |doi= }}
* {{cite journal | vauthors = Hospattankar AV, Brewer HB, Ronan R, Fairwell T | title = Amino acid sequence of human plasma apolipoprotein C-III from normolipidemic subjects | journal = FEBS Letters | volume = 197 | issue = 1–2 | pages = 67–73 | date = Mar 1986 | pmid = 3949020 | doi = 10.1016/0014-5793(86)80300-3 }}
*{{cite journal | author=Karathanasis SK, Zannis VI, Breslow JL |title=Isolation and characterization of cDNA clones corresponding to two different human apoC-III alleles. |journal=J. Lipid Res. |volume=26 |issue= 4 |pages= 451-6 |year= 1985 |pmid= 2989400 |doi=  }}
* {{cite journal | vauthors = Brewer HB, Shulman R, Herbert P, Ronan R, Wehrly K | title = The complete amino acid sequence of alanine apolipoprotein (apoC-3), and apolipoprotein from human plasma very low density lipoproteins | journal = The Journal of Biological Chemistry | volume = 249 | issue = 15 | pages = 4975–84 | date = Aug 1974 | pmid = 4846755 }}
*{{cite journal | author=Karathanasis SK, Oettgen P, Haddad IA, Antonarakis SE |title=Structure, evolution, and polymorphisms of the human apolipoprotein A4 gene (APOA4). |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=83 |issue= 22 |pages= 8457-61 |year= 1986 |pmid= 3095836 |doi= }}
* {{cite journal | vauthors = Karathanasis SK, McPherson J, Zannis VI, Breslow JL | title = Linkage of human apolipoproteins A-I and C-III genes | journal = Nature | volume = 304 | issue = 5924 | pages = 371–73 | year = 1983 | pmid = 6308458 | doi = 10.1038/304371a0 }}
*{{cite journal | author=Maeda H, Hashimoto RK, Ogura T, ''et al.'' |title=Molecular cloning of a human apoC-III variant: Thr 74----Ala 74 mutation prevents O-glycosylation. |journal=J. Lipid Res. |volume=28 |issue= 12 |pages= 1405-9 |year= 1988 |pmid= 3123586 |doi= }}
* {{cite journal | vauthors = Sharpe CR, Sidoli A, Shelley CS, Lucero MA, Shoulders CC, Baralle FE | title = Human apolipoproteins AI, AII, CII and CIII. cDNA sequences and mRNA abundance | journal = Nucleic Acids Research | volume = 12 | issue = 9 | pages = 3917–32 | date = May 1984 | pmid = 6328445 | pmc = 318799 | doi = 10.1093/nar/12.9.3917 }}
*{{cite journal | author=Karathanasis SK |title=Apolipoprotein multigene family: tandem organization of human apolipoprotein AI, CIII, and AIV genes. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=82 |issue= 19 |pages= 6374-8 |year= 1985 |pmid= 3931073 |doi= }}
* {{cite journal | vauthors = Law SW, Gray G, Brewer HB | title = cDNA cloning of human apoA-I: amino acid sequence of preproapoA-I | journal = Biochemical and Biophysical Research Communications | volume = 112 | issue = 1 | pages = 257–64 | date = Apr 1983 | pmid = 6404278 | doi = 10.1016/0006-291X(83)91824-7 }}
*{{cite journal | author=Zannis VI, Cole FS, Jackson CL, ''et al.'' |title=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. |journal=Biochemistry |volume=24 |issue= 16 |pages= 4450-5 |year= 1985 |pmid= 3931677 |doi= }}
* {{cite journal | vauthors = Protter AA, Levy-Wilson B, Miller J, Bencen G, White T, Seilhamer JJ | title = Isolation and sequence analysis of the human apolipoprotein CIII gene and the intergenic region between the apo AI and apo CIII genes | journal = Dna | volume = 3 | issue = 6 | pages = 449–56 | date = Dec 1984 | pmid = 6439535 | doi = 10.1089/dna.1.1984.3.449 }}
*{{cite journal | author=Shelley CS, Sharpe CR, Baralle FE, Shoulders CC |title=Comparison of the human apolipoprotein genes. Apo AII presents a unique functional intron-exon junction. |journal=J. Mol. Biol. |volume=186 |issue= 1 |pages= 43-51 |year= 1986 |pmid= 3935800 |doi=  }}
* {{cite journal | vauthors = Levy-Wilson B, Appleby V, Protter A, Auperin D, Seilhamer JJ | title = Isolation and DNA sequence of full-length cDNA for human preapolipoprotein CIII | journal = Dna | volume = 3 | issue = 5 | pages = 359–64 | date = Oct 1984 | pmid = 6548954 | doi = 10.1089/dna.1984.3.359 }}
*{{cite journal | author=Hospattankar AV, Brewer HB, Ronan R, Fairwell T |title=Amino acid sequence of human plasma apolipoprotein C-III from normolipidemic subjects. |journal=FEBS Lett. |volume=197 |issue= 1-2 |pages= 67-73 |year= 1986 |pmid= 3949020 |doi= }}
* {{cite journal | vauthors = Dammerman M, Sandkuijl LA, Halaas JL, Chung W, Breslow JL | title = An apolipoprotein CIII haplotype protective against hypertriglyceridemia is specified by promoter and 3' untranslated region polymorphisms | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 10 | pages = 4562–66 | date = May 1993 | pmid = 8099442 | pmc = 46552 | doi = 10.1073/pnas.90.10.4562 }}
*{{cite journal | author=Brewer HB, Shulman R, Herbert P, ''et al.'' |title=The complete amino acid sequence of alanine apolipoprotein (apoC-3), and apolipoprotein from human plasma very low density lipoproteins. |journal=J. Biol. Chem. |volume=249 |issue= 15 |pages= 4975-84 |year= 1974 |pmid= 4846755 |doi= }}
* {{cite journal | vauthors = Wu JH, Kao JT, Wen MS, Lo SK | title = DNA polymorphisms at the apolipoprotein A1-CIII loci in Taiwanese: correlation of plasma APOCIII with triglyceride level and body mass index | journal = Journal of the Formosan Medical Association = Taiwan Yi Zhi | volume = 99 | issue = 5 | pages = 367–74 | date = May 2000 | pmid = 10870325 }}
*{{cite journal | author=Karathanasis SK, McPherson J, Zannis VI, Breslow JL |title=Linkage of human apolipoproteins A-I and C-III genes. |journal=Nature |volume=304 |issue= 5924 |pages= 371-3 |year= 1983 |pmid= 6308458 |doi= }}
* {{cite journal | vauthors = Geraci MW, Moore M, Gesell T, Yeager ME, Alger L, Golpon H, Gao B, Loyd JE, Tuder RM, Voelkel NF | title = Gene expression patterns in the lungs of patients with primary pulmonary hypertension: a gene microarray analysis | journal = Circulation Research | volume = 88 | issue = 6 | pages = 555–62 | date = Mar 2001 | pmid = 11282888 | doi = 10.1161/01.RES.88.6.555 }}
*{{cite journal | author=Sharpe CR, Sidoli A, Shelley CS, ''et al.'' |title=Human apolipoproteins AI, AII, CII and CIII. cDNA sequences and mRNA abundance. |journal=Nucleic Acids Res. |volume=12 |issue= 9 |pages= 3917-32 |year= 1984 |pmid= 6328445 |doi= }}
* {{cite journal | vauthors = Inoue Y, Miyazaki M, Tsuji T, Sakaguchi M, Fukaya K, Huh NH, Namba M | title = Reactivation of liver-specific gene expression in an immortalized human hepatocyte cell line by introduction of the human HNF4alpha2 gene | journal = International Journal of Molecular Medicine | volume = 8 | issue = 5 | pages = 481–87 | date = Nov 2001 | pmid = 11605014 | doi = 10.3892/ijmm.8.5.481 }}
*{{cite journal | author=Law SW, Gray G, Brewer HB |title=cDNA cloning of human apoA-I: amino acid sequence of preproapoA-I. |journal=Biochem. Biophys. Res. Commun. |volume=112 |issue= 1 |pages= 257-64 |year= 1983 |pmid= 6404278 |doi= }}
* {{cite journal | vauthors = Pastier D, Lacorte JM, Chambaz J, Cardot P, Ribeiro A | title = 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 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 17 | pages = 15199–206 | date = Apr 2002 | pmid = 11839757 | doi = 10.1074/jbc.M200227200 }}
*{{cite journal | author=Protter AA, Levy-Wilson B, Miller J, ''et al.'' |title=Isolation and sequence analysis of the human apolipoprotein CIII gene and the intergenic region between the apo AI and apo CIII genes. |journal=DNA |volume=3 |issue= 6 |pages= 449-56 |year= 1985 |pmid= 6439535 |doi= }}
* {{cite journal | vauthors = Chhabra S, Narang R, Krishnan LR, Vasisht S, Agarwal DP, Srivastava LM, Manchanda SC, Das N | title = Apolipoprotein C3 SstI polymorphism and triglyceride levels in Asian Indians | journal = BMC Genetics | volume = 3 | page = 9 | date = Jun 2002 | pmid = 12052247 | pmc = 116591 | doi = 10.1186/1471-2156-3-9 | url = http://www.biomedcentral.com/1471-2156/3/9 }}
*{{cite journal | author=Levy-Wilson B, Appleby V, Protter A, ''et al.'' |title=Isolation and DNA sequence of full-length cDNA for human preapolipoprotein CIII. |journal=DNA |volume=3 |issue= 5 |pages= 359-64 |year= 1985 |pmid= 6548954 |doi=  }}
*{{cite journal | author=Dammerman M, Sandkuijl LA, Halaas JL, ''et al.'' |title=An apolipoprotein CIII haplotype protective against hypertriglyceridemia is specified by promoter and 3' untranslated region polymorphisms. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=90 |issue= 10 |pages= 4562-6 |year= 1993 |pmid= 8099442 |doi= }}
*{{cite journal | author=Wu JH, Kao JT, Wen MS, Lo SK |title=DNA polymorphisms at the apolipoprotein A1-CIII loci in Taiwanese: correlation of plasma APOCIII with triglyceride level and body mass index. |journal=J. Formos. Med. Assoc. |volume=99 |issue= 5 |pages= 367-74 |year= 2000 |pmid= 10870325 |doi= }}
*{{cite journal | author=Geraci MW, Moore M, Gesell T, ''et al.'' |title=Gene expression patterns in the lungs of patients with primary pulmonary hypertension: a gene microarray analysis. |journal=Circ. Res. |volume=88 |issue= 6 |pages= 555-62 |year= 2001 |pmid= 11282888 |doi= }}
*{{cite journal | author=Inoue Y, Miyazaki M, Tsuji T, ''et al.'' |title=Reactivation of liver-specific gene expression in an immortalized human hepatocyte cell line by introduction of the human HNF4alpha2 gene. |journal=Int. J. Mol. Med. |volume=8 |issue= 5 |pages= 481-7 |year= 2002 |pmid= 11605014 |doi= }}
*{{cite journal  | author=Pastier D, Lacorte JM, Chambaz J, ''et al.'' |title=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. |journal=J. Biol. Chem. |volume=277 |issue= 17 |pages= 15199-206 |year= 2002 |pmid= 11839757 |doi= 10.1074/jbc.M200227200 }}
*{{cite journal  | author=Chhabra S, Narang R, Krishnan LR, ''et al.'' |title=Apolipoprotein C3 SstI polymorphism and triglyceride levels in Asian Indians. |journal=BMC Genet. |volume=3 |issue=  |pages= 9 |year= 2002 |pmid= 12052247 |doi=  }}
}}
{{refend}}
{{refend}}
{{protein-stub}}


{{Lipoproteins}}
{{Lipoproteins}}


[[Category:Apolipoproteins]]
[[Category:Apolipoproteins]]
[[ru:Аполипопротеин C3]]

Revision as of 01:42, 9 July 2017

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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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 a component of very low density lipoprotein (VLDL).

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.[1] 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.[2]

Function

APOC3 inhibits lipoprotein lipase and hepatic lipase; it is thought to inhibit hepatic uptake[3] 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.[4] 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.[5][6]

Clinical significance

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[7] as well as non-insulin diabetes mellitus.[8] 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).[9]

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.[10]

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.[11] Interestingly, 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. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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

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