FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2475024711> ?p ?o ?g. }

• W2475024711 endingPage "1607" @default.
• W2475024711 startingPage "1601" @default.
• W2475024711 abstract "LPL contributes profoundly to physiologic lipoprotein metabolism and to tissue-specific substrate delivery and utilization (1.Wang H. Eckel R.H. Lipoprotein lipase: from gene to obesity.Am. J. Physiol. Endocrinol. Metab. 2009; 297: E271-E288Crossref PubMed Scopus (575) Google Scholar). Perturbed LPL activity affects global energy balance, insulin action, body weight maintenance, and CVD risk; the latter alluded to by contemporary human genetic studies. LPL is the pivotal rate-limiting mediator of hydrolysis of core TGs from TG-rich lipoproteins, particularly chylomicrons and VLDL (2.Kersten S. Physiological regulation of lipoprotein lipase.Biochim. Biophys. Acta. 2014; 1841: 919-933Crossref PubMed Scopus (346) Google Scholar, 3.Olivecrona G. Role of lipoprotein lipase in lipid metabolism.Curr. Opin. Lipidol. 2016; 27: 233-241Crossref PubMed Scopus (130) Google Scholar). The products of LPL-mediated catalysis, such as fatty acids and monoacylglycerol, are handled differentially at local sites depending on the global hormonal and nutritional milieu, and local energy needs. For instance, in the fasted state, LPL activity in adipose tissue is suppressed, while it is increased in skeletal and cardiac muscle, shunting fatty acids away from storage and toward utilization in heavily oxidizing tissues. Conversely, after eating, LPL activity in adipose tissue is enhanced, while it is suppressed in skeletal and cardiac muscles, shunting fatty acids toward storage. Similar tissue-specific modulation of LPL activity is related to cold and exercise (1.Wang H. Eckel R.H. Lipoprotein lipase: from gene to obesity.Am. J. Physiol. Endocrinol. Metab. 2009; 297: E271-E288Crossref PubMed Scopus (575) Google Scholar, 2.Kersten S. Physiological regulation of lipoprotein lipase.Biochim. Biophys. Acta. 2014; 1841: 919-933Crossref PubMed Scopus (346) Google Scholar, 3.Olivecrona G. Role of lipoprotein lipase in lipid metabolism.Curr. Opin. Lipidol. 2016; 27: 233-241Crossref PubMed Scopus (130) Google Scholar, 4.Brown W.V. Goldberg I.J. Young S.G. JCL roundtable: hypertriglyceridemia due to defects in lipoprotein lipase function.J. Clin. Lipidol. 2015; 9: 274-280Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). Recently, the complexity of the regulation of LPL secretion and activity has become more apparent; some insights have emerged from studying natural human genetic variants. LPL is regulated at transcriptional, posttranscriptional, and posttranslational levels (1.Wang H. Eckel R.H. Lipoprotein lipase: from gene to obesity.Am. J. Physiol. Endocrinol. Metab. 2009; 297: E271-E288Crossref PubMed Scopus (575) Google Scholar, 2.Kersten S. Physiological regulation of lipoprotein lipase.Biochim. Biophys. Acta. 2014; 1841: 919-933Crossref PubMed Scopus (346) Google Scholar, 3.Olivecrona G. Role of lipoprotein lipase in lipid metabolism.Curr. Opin. Lipidol. 2016; 27: 233-241Crossref PubMed Scopus (130) Google Scholar, 4.Brown W.V. Goldberg I.J. Young S.G. JCL roundtable: hypertriglyceridemia due to defects in lipoprotein lipase function.J. Clin. Lipidol. 2015; 9: 274-280Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar); furthermore, depending on local milieu and needs, this regulation is tissue specific. At least 10 gene products govern the secretion and activity of LPL at different stages of its life cycle. LPL is primarily expressed in tissues that oxidize or store fatty acids in large quantities, such as the heart, skeletal muscle, and brown and white adipose tissue. Although various factors influence LPL gene transcription (1.Wang H. Eckel R.H. Lipoprotein lipase: from gene to obesity.Am. J. Physiol. Endocrinol. Metab. 2009; 297: E271-E288Crossref PubMed Scopus (575) Google Scholar, 2.Kersten S. Physiological regulation of lipoprotein lipase.Biochim. Biophys. Acta. 2014; 1841: 919-933Crossref PubMed Scopus (346) Google Scholar, 3.Olivecrona G. Role of lipoprotein lipase in lipid metabolism.Curr. Opin. Lipidol. 2016; 27: 233-241Crossref PubMed Scopus (130) Google Scholar, 4.Brown W.V. Goldberg I.J. Young S.G. JCL roundtable: hypertriglyceridemia due to defects in lipoprotein lipase function.J. Clin. Lipidol. 2015; 9: 274-280Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar), much of the physiological variation in LPL activity, i.e., related to feeding-fasting cycles and exercise, appears to be driven via posttranslational mechanisms by extracellular proteins. These proteins can be divided into two main groups: the liver-derived apolipoproteins, which are products of the APOC1, APOC2, APOE, APOC3, and APOA5 genes, and the more broadly expressed angiopoietin-like (ANGPTL) proteins, specifically the products of the ANGPTL3, ANGPTL4, and ANGPTL8 genes. But even prior to regulation by apolipoproteins and ANGPTL proteins, LPL secretion and delivery to the vascular space is in the hands of other intermediaries, including products of lipase maturation factor 1 (LMF1) and glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1 (GPIHBP1) genes. In addition to classical cellular and molecular biological studies of these various proteins, studies of naturally occurring human genetic variants have helped fill in some gaps in understanding of LPL regulation. Selected information regarding genes affecting LPL discussed below is summarized in Table 1.TABLE 1Selected gene products that interact with LPL and their genetic associations with plasma lipids and CHD riskProteinGene Symbol/Chromosomal PositionEffect on LPL ActivityBiochemical PhenotypesCHD AssociationRare VariantsCommon VariantsLPLLPL/8p21.3ReferenceHmz LOF: chylomicronemiaLOF: higher TG, lower HDL-CCommon LOF: increased CHD riskHet LOF: increased risk of severe HTGGOF: lower TG, higher HDL-CCommon GOF: reduced CHD riskRare LOF Het: likely increased CHD riskRare LOF Hmz: noneLMF1LMF1/16p13.3PromotesHmz LOF: chylomicronemiaGWAS: noneCommon or rare: noneHet LOF: increased risk of severe HTGGPIHBP1GPIHBP1/8q24.3PromotesHmz LOF: chylomicronemiaGWAS: noneCommon or rare: noneHet LOF: increased risk of severe HTGapoC-IAPOC1/19q13.3InhibitsHet LOF: reduced TGGWAS: noneCommon or rare: noneapoC-IIAPOC2/19q13.3PromotesHmz LOF: chylomicronemiaGWAS: noneCommon or rare: noneHet LOF: increased risk of severe HTGapoEAPOE/19q13.3E2 isoform inhibitsHet rare LOF variants: dysbetalipoproteinemiaHmz E2 plus 2° factors: dysbetalipoproteinemiaE2 Het or Hmz without dysbetalipoproteinemia: neutral or reduced CHD riskE2 Hmz in dysbetalipoproteinemia: increased CHD riskapoC-IIIAPOC3/11q23.3InhibitsHet LOF: reduced TG, increased HDL-CGOF from candidate gene studies: higher TG, lower HDL-CCommon GOF: increased risk MR rare Het LOF: reduced CHD riskapoA-VAPOA5/11q23.3PromotesHmz LOF: chylomicronemiaLOF from GWAS: higher TG; lower HDL-CCommon Het LOF: increased CHD riskHet LOF: increased risk of severe HTGMR rare Het LOF: increased CHD riskANGPTL3ANGPTL3/1p31.3InhibitsHmz LOF: familial combined hypolipidemiaGWAS: lower LDL-C, HDL-C, TGCommon or rare: noneANGPTL4ANGPTL4/19p13.2InhibitsHet LOF: reduced TG, increased HDL-CGWAS: reduced TG, increased HDL-CCommon LOF: reduced CHD riskRare Het LOF: reduced CHD riskANGPTL8ANGPTL8/19p13.2InhibitsHet LOF: reduced TG, increased HDL-CGWAS: noneCommon or rare: noneHmz, homozygous (can also refer here to compound heterozygous, or different mutations on two alleles); Het, simple heterozygous; LOF, loss-of-function; GOF, gain-of-function; HTG, hypertriglyceridemia; HDL-C, HDL cholesterol; TG, triglyceride; GWAS, genome-wide association study results; MR, Mendelian randomization study results. Open table in a new tab Hmz, homozygous (can also refer here to compound heterozygous, or different mutations on two alleles); Het, simple heterozygous; LOF, loss-of-function; GOF, gain-of-function; HTG, hypertriglyceridemia; HDL-C, HDL cholesterol; TG, triglyceride; GWAS, genome-wide association study results; MR, Mendelian randomization study results. The central nonredundant role of basal LPL mass and activity in directing intravascular hydrolysis of TG-rich lipoproteins is underscored by the causative role of very rare homozygous loss-of-function variants in the LPL gene in patients with severe hypertriglyceridemia (essentially chylomicronemia) and increased risk of pancreatitis (5.Rodrigues R. Artieda M. Tejedor D. Martinez A. Konstantinova P. Petry H. Meyer C. Corzo D. Sundgreen C. Klor H.U. et al.Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency.J. Clin. Lipidol. 2016; 10: 394-409Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 6.Brahm A.J. Hegele R.A. Chylomicronaemia–current diagnosis and future therapies.Nat. Rev. Endocrinol. 2015; 11: 352-362Crossref PubMed Scopus (212) Google Scholar). About 40% of patients diagnosed clinically with LPL deficiency have rare loss-of-function variants on both LPL alleles (5.Rodrigues R. Artieda M. Tejedor D. Martinez A. Konstantinova P. Petry H. Meyer C. Corzo D. Sundgreen C. Klor H.U. et al.Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency.J. Clin. Lipidol. 2016; 10: 394-409Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar); among all patients with severe hypertriglyceridemia, ~10% have one or two probable pathogenic LPL variants. Rare instances of atherosclerosis observed in patients with complete LPL deficiency are exceptions that seem to prove the rule that severe chylomicronemia due to complete LPL deficiency is not associated with increased atherosclerosis risk (7.Benlian P. De Gennes J.L. Foubert L. Zhang H. Gagne S.E. Hayden M. Premature atherosclerosis in patients with familial chylomicronemia caused by mutations in the lipoprotein lipase gene.N. Engl. J. Med. 1996; 335: 848-854Crossref PubMed Scopus (271) Google Scholar). Heterozygotes for these loss-of-function variants are overrepresented in pools of patients with severe hypertriglyceridemia (formerly type 5 hyperlipoproteinemia) who do not have classical LPL deficiency (8.Johansen C.T. Wang J. Lanktree M.B. Cao H. McIntyre A.D. Ban M.R. Martins R.A. Kennedy B.A. Hassell R.G. Visser M.E. et al.Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia.Nat. Genet. 2010; 42: 684-687Crossref PubMed Scopus (373) Google Scholar). In contrast, common small-effect LPL loss-of-function variants in the general population are associated with milder increases in plasma TGs, due in part to impaired clearance of VLDL (5.Rodrigues R. Artieda M. Tejedor D. Martinez A. Konstantinova P. Petry H. Meyer C. Corzo D. Sundgreen C. Klor H.U. et al.Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency.J. Clin. Lipidol. 2016; 10: 394-409Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). Furthermore, common LPL genetic variants that slightly raise TGs and lower HDL cholesterol are associated with increased coronary heart disease (CHD) risk, while a common LPL gain-of-function variant that modestly lowers TGs and raises HDL cholesterol has repeatedly been associated with protection from CHD (9.Sagoo G.S. Tatt I. Salanti G. Butterworth A.S. Sarwar N. van Maarle M. Jukema J.W. Wiman B. Kastelein J.J. Bennet A.M. et al.Seven lipoprotein lipase gene polymorphisms, lipid fractions, and coronary disease: a HuGE association review and meta-analysis.Am. J. Epidemiol. 2008; 168: 1233-1246Crossref PubMed Scopus (107) Google Scholar, 10.Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease.N. Engl. J. Med. 2016; 374: 1134-1144Crossref PubMed Scopus (344) Google Scholar). Such genetic findings, in addition to consistently demonstrating the modestly altered biochemical phenotype, increasingly implicate partially altered LPL function as a determinant of CHD risk. A question that emerges is “do genetic variants in the interacting proteins impact on CHD risk in a manner consistent with their predicted effects on LPL?” Before its intravascular lipolytic activity undergoes in situ regulation, LPL needs to arrive safely at the endothelial surface of vasculature from its site of synthesis within various cell types, such as adipocytes or skeletal muscle. LMF1, encoded by the LMF1 gene, is a membrane-bound chaperone protein located in the endoplasmic reticulum that is essential for the proper folding and assembly not only of LPL, but also of hepatic lipase and endothelial lipase (11.Doolittle M.H. Ehrhardt N. Peterfy M. Lipase maturation factor 1: structure and role in lipase folding and assembly.Curr. Opin. Lipidol. 2010; 21: 198-203Crossref PubMed Scopus (47) Google Scholar). The involvement of LMF1 in the activity of multiple lipases is consistent with its implication initially as the causative gene for murine combined lipase deficiency (11.Doolittle M.H. Ehrhardt N. Peterfy M. Lipase maturation factor 1: structure and role in lipase folding and assembly.Curr. Opin. Lipidol. 2010; 21: 198-203Crossref PubMed Scopus (47) Google Scholar, 12.Péterfy M. Lipase maturation factor 1: a lipase chaperone involved in lipid metabolism.Biochim. Biophys. Acta. 2012; 1821: 790-794Crossref PubMed Scopus (60) Google Scholar). As LMF1 participates exclusively in the maturation of homodimeric lipases, but not monomeric lipases, it probably mediates the assembly of inactive lipase subunits into active enzymes and may stabilize the active dimers (11.Doolittle M.H. Ehrhardt N. Peterfy M. Lipase maturation factor 1: structure and role in lipase folding and assembly.Curr. Opin. Lipidol. 2010; 21: 198-203Crossref PubMed Scopus (47) Google Scholar, 12.Péterfy M. Lipase maturation factor 1: a lipase chaperone involved in lipid metabolism.Biochim. Biophys. Acta. 2012; 1821: 790-794Crossref PubMed Scopus (60) Google Scholar). Rare genetic variants in LMF1 are associated with severe hypertriglyceridemia (chylomicronemia) in mice and humans, due to impaired lipid clearance from lipase deficiency (12.Péterfy M. Lipase maturation factor 1: a lipase chaperone involved in lipid metabolism.Biochim. Biophys. Acta. 2012; 1821: 790-794Crossref PubMed Scopus (60) Google Scholar). Interestingly, common variants in LMF1 have not been reported as being associated with either altered plasma lipoproteins or atherosclerosis in genome-wide association studies in populations. After LPL is secreted from parenchymal cells, it needs to reach the endothelial cell surface. GPIHBP1, encoded by the GPIHBP1 gene, seizes LPL in the interstitial space (13.Young S.G. Davies B.S. Voss C.V. Gin P. Weinstein M.M. Tontonoz P. Reue K. Bensadoun A. Fong L.G. Beigneux A.P. GPIHBP1, an endothelial cell transporter for lipoprotein lipase.J. Lipid Res. 2011; 52: 1869-1884Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 14.Adeyo O. Goulbourne C.N. Bensadoun A. Beigneux A.P. Fong L.G. Young S.G. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 and the intravascular processing of triglyceride-rich lipoproteins.J. Intern. Med. 2012; 272: 528-540Crossref PubMed Scopus (33) Google Scholar) and shuttles it across endothelial cells to the lumenal surface; it also tethers LPL to the capillary endothelium (15.Young S.G. Zechner R. Biochemistry and pathophysiology of intravascular and intracellular lipolysis.Genes Dev. 2013; 27: 459-484Crossref PubMed Scopus (244) Google Scholar). The reader is referred to the beautiful work from Young (15.Young S.G. Zechner R. Biochemistry and pathophysiology of intravascular and intracellular lipolysis.Genes Dev. 2013; 27: 459-484Crossref PubMed Scopus (244) Google Scholar) in defining the structure and function of this fascinating protein. The essential role of GPIHBP1 in handling LPL is emphasized by the consequences of rare homozygous genetic variants that compromise GPIHBP1 function, including impairing its ability to bind LPL, resulting in mislocalization of LPL in the interstitial space and consequent severe hypertriglyceridemia (chylomicronemia). As with LMF1, there is no evidence that milder common heterozygous variants within GPIHBP1 are associated with either altered plasma lipoproteins or atherosclerosis in genome-wide association studies in populations. Several apolipoproteins exert direct and indirect effects on LPL once it settles upon its site of action. apoC-I is the product of the APOC1 gene on chromosome 19. The human APOC1 transgenic mouse has combined hyperlipidemia (16.Shachter N.S. Ebara T. Ramakrishnan R. Steiner G. Breslow J.L. Ginsberg H.N. Smith J.D. Combined hyperlipidemia in transgenic mice overexpressing human apolipoprotein Cl.J. Clin. Invest. 1996; 98: 846-855Crossref PubMed Scopus (99) Google Scholar). apoC-I has been reported to inhibit LPL activity by preventing binding of LPL to the lipid-water interface of TG-rich lipoproteins and also by rendering LPL more susceptible to interference by ANGPTL4 (17.Larsson M. Vorrsjo E. Talmud P. Lookene A. Olivecrona G. Apolipoproteins C–I and C–III inhibit lipoprotein lipase activity by displacement of the enzyme from lipid droplets.J. Biol. Chem. 2013; 288: 33997-34008Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). Recently, a rare variant (allele frequency 0.82%) in a noncoding region of APOC1 was associated with a 13.6% reduction in plasma TG, but with no change in CHD risk (18.Helgadottir A. Gretarsdottir S. Thorleifsson G. Hjartarson E. Sigurdsson A. Magnusdottir A. Jonasdottir A. Kristjansson H. Sulem P. Oddsson A. et al.Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease.Nat. Genet. 2016; 48: 634-639Crossref PubMed Scopus (168) Google Scholar). Tangentially, a relatively common APOC1 missense variant (p.T45S) seen only in North American indigenous people was associated with lower body mass index (19.Lahiry P. Cao H. Ban M.R. Pollex R.L. Mamakeesick M. Zinman B. Harris S.B. Hanley A.J. Huff M.W. Connelly P.W. et al.APOC1 T45S polymorphism is associated with reduced obesity indices and lower plasma concentrations of leptin and apolipoprotein C-I in aboriginal Canadians.J. Lipid Res. 2010; 51: 843-848Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). apoC-II is a constituent of chylomicrons, VLDL, LDL, and HDL particles. apoC-II contains three amphipathic α-helices, an N-terminal lipid binding domain, and a C-terminal LPL binding domain (20.Kei A.A. Filippatos T.D. Tsimihodimos V. Elisaf M.S. A review of the role of apolipoprotein C-II in lipoprotein metabolism and cardiovascular disease.Metabolism. 2012; 61: 906-921Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). It is an essential cofactor for LPL activity; homozygous rare loss-of-function variants in APOC2 leading to apoC-II deficiency are associated with a chylomicronemia phenotype that resembles LPL deficiency (21.Cox D.W. Breckenridge W.C. Little J.A. Inheritance of apolipoprotein C-II deficiency with hypertriglyceridemia and pancreatitis.N. Engl. J. Med. 1978; 299: 1421-1424Crossref PubMed Scopus (116) Google Scholar). Perhaps paradoxically, apoC-II concentrations are elevated in hypertriglyceridemia (22.Schonfeld G. George P.K. Miller J. Reilly P. Witztum J. Apolipoprotein C-II and C–III levels in hyperlipoproteinemia.Metabolism. 1979; 28: 1001-1010Abstract Full Text PDF PubMed Scopus (144) Google Scholar); overexpression of apoC-II in animal models also leads to severe hypertriglyceridemia (23.Shachter N.S. Hayek T. Leff T. Smith J.D. Rosenberg D.W. Walsh A. Ramakrishnan R. Goldberg I.J. Ginsberg H.N. Breslow J.L. Overexpression of apolipoprotein CII causes hypertriglyceridemia in transgenic mice.J. Clin. Invest. 1994; 93: 1683-1690Crossref PubMed Scopus (119) Google Scholar), although an analogous situation in humans has not been observed. Rare heterozygous APOC2 variants are among those that are overrepresented in pools of patients with severe hypertriglyceridemia (24.Johansen C.T. Wang J. McIntyre A.D. Martins R.A. Ban M.R. Lanktree M.B. Huff M.W. Peterfy M. Mehrabian M. Lusis A.J. et al.Excess of rare variants in non-genome-wide association study candidate genes in patients with hypertriglyceridemia.Circ Cardiovasc Genet. 2012; 5: 66-72Crossref PubMed Scopus (67) Google Scholar), but not with increased CVD risk. There is no evidence that common APOC2 variants are associated with either altered plasma lipoproteins or atherosclerosis in genome-wide association studies. apoE, encoded by the APOE gene, is a component of TG-rich lipoproteins, their remnants, and HDL (25.Phillips M.C. Apolipoprotein E isoforms and lipoprotein metabolism.IUBMB Life. 2014; 66: 616-623Crossref PubMed Scopus (186) Google Scholar). Common polymorphisms at two sites in the APOE coding sequence underlie the classical apoE protein isoform system: E4 (arginine at both residues 112 and 158, without counting the prepeptide sequence; otherwise these are residues 130 and 176), E3 (cysteine at residue 112, arginine at residue 158), and E2 (cysteine at both residues 112 and 158). Homozygosity for the E2 isoform, in the context of additional genetic or nongenetic factors, can be associated with hyperlipidemia, characterized by increased plasma levels of chylomicron and VLDL remnants, associated with xanthomatosis and early atherosclerosis (26.Hegele R.A. Ban M.R. Hsueh N. Kennedy B.A. Cao H. Zou G.Y. Anand S. Yusuf S. Huff M.W. Wang J. A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia.Hum. Mol. Genet. 2009; 18: 4189-4194Crossref PubMed Scopus (83) Google Scholar). In this pathological state, E2-containing particles accumulate in plasma: increased plasma cholesterol in these patients results from impaired clearance of E2-bearing particles, while increased TG is caused by interference with LPL by E2 (27.Huang Y. Liu X.Q. Rall Jr, S.C. Mahley R.W. Apolipoprotein E2 reduces the low density lipoprotein level in transgenic mice by impairing lipoprotein lipase-mediated lipolysis of triglyceride-rich lipoproteins.J. Biol. Chem. 1998; 273: 17483-17490Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). The hypertriglyceridemia in E2 transgenic mice can be corrected by directly activating LPL by overexpressing apoA-V, but not by deleting apoC-III (28.Gerritsen G. van der Hoogt C.C. Schaap F.G. Voshol P.J. Kypreos K.E. Maeda N. Groen A.K. Havekes L.M. Rensen P.C. van Dijk K.W. ApoE2-associated hypertriglyceridemia is ameliorated by increased levels of apoA-V but unaffected by apoC-III deficiency.J. Lipid Res. 2008; 49: 1048-1055Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar). Also, there are a few ultra-rare apoE protein coding variants that can have dominant effects on the lipid phenotype, also with an associated increased CHD risk (29.Hegele R.A. Plasma lipoproteins: genetic influences and clinical implications.Nat. Rev. Genet. 2009; 10: 109-121Crossref PubMed Scopus (326) Google Scholar). apoC-III, encoded by the APOC3 gene, is a constituent of several apoB-containing lipoproteins, including chylomicrons, VLDL and LDL, and also HDL particles (30.Norata G.D. Tsimikas S. Pirillo A. Catapano A.L. Apolipoprotein C-III: from pathophysiology to pharmacology.Trends Pharmacol. Sci. 2015; 36: 675-687Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar). Like apoC-I, apoC-III may inhibit LPL activity by preventing binding of LPL to the lipid-water interface of TG-rich lipoproteins and also by rendering LPL more susceptible to interference by ANGPTL4 (17.Larsson M. Vorrsjo E. Talmud P. Lookene A. Olivecrona G. Apolipoproteins C–I and C–III inhibit lipoprotein lipase activity by displacement of the enzyme from lipid droplets.J. Biol. Chem. 2013; 288: 33997-34008Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). There is also substantial evidence that apoC-III plays a role in hepatic TG-rich lipoprotein production (31.Yao Z. Wang Y. Apolipoprotein C-III and hepatic triglyceride-rich lipoprotein production.Curr. Opin. Lipidol. 2012; 23: 206-212Crossref PubMed Scopus (77) Google Scholar). Transgenic overexpression of human APOC3 in mice is associated with severe hypertriglyceridemia (32.Ito Y. Azrolan N. O'Connell A. Walsh A. Breslow J.L. Hypertriglyceridemia as a result of human apo CIII gene expression in transgenic mice.Science. 1990; 249: 790-793Crossref PubMed Scopus (451) Google Scholar), while targeted deletion of murine Apoc3 is associated with low TG and protection from postprandial hypertriglyceridemia (33.Maeda N. Li H. Lee D. Oliver P. Quarfordt S.H. Osada J. Targeted disruption of the apolipoprotein C-III gene in mice results in hypotriglyceridemia and protection from postprandial hypertriglyceridemia.J. Biol. Chem. 1994; 269: 23610-23616Abstract Full Text PDF PubMed Google Scholar). Rare loss-of-function variants of APOC3 are associated with moderately reduced TG, increased HDL cholesterol, and reduced CHD risk (34.Pollin T.I. Damcott C.M. Shen H. Ott S.H. Shelton J. Horenstein R.B. Post W. McLenithan J.C. Bielak L.F. Peyser P.A. et al.A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection.Science. 2008; 322: 1702-1705Crossref PubMed Scopus (523) Google Scholar, 35.Crosby J. Peloso G.M. Auer P.L. Crosslin D.R. Stitziel N.O. Lange L.A. Lu Y. Tang Z.Z. Zhang H. Hindy G. et al.Loss-of-function mutations in APOC3, triglycerides, and coronary disease.N. Engl. J. Med. 2014; 371: 22-31Crossref PubMed Scopus (760) Google Scholar, 36.Jørgensen A.B. Frikke-Schmidt R. Nordestgaard B.G. Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease.N. Engl. J. Med. 2014; 371: 32-41Crossref PubMed Scopus (642) Google Scholar). Common variants in APOC3, particularly those in the promoter associated with failure to downregulate in the presence of insulin (37.Li W.W. Dammerman M.M. Smith J.D. Metzger S. Breslow J.L. Leff T. Common genetic variation in the promoter of the human apo CIII gene abolishes regulation by insulin and may contribute to hypertriglyceridemia.J. Clin. Invest. 1995; 96: 2601-2605Crossref PubMed Scopus (242) Google Scholar), have been associated with elevated TG and reduced HDL cholesterol (38.Hegele R.A. Connelly P.W. Hanley A.J. Sun F. Harris S.B. Zinman B. Common genomic variation in the APOC3 promoter associated with variation in plasma lipoproteins.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 2753-2758Crossref PubMed Scopus (73) Google Scholar). Thus, the human genetic data support a functional role for apoC-III in modulating both plasma lipoproteins and CHD risk in a manner that reflects the association of LPL genetic variation with these traits. Although the predominant opinion had been that apoC-III raised plasma TGs primarily by inhibiting LPL activity (39.Gaudet D. Alexander V.J. Baker B.F. Brisson D. Tremblay K. Singleton W. Geary R.S. Hughes S.G. Viney N.J. Graham M.J. et al.Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia.N. Engl. J. Med. 2015; 373: 438-447Crossref PubMed Scopus (394) Google Scholar), the recent demonstration that antisense-mediated suppression of apoC-III plasma levels in patients with familial chylomicronemia syndrome, who had no measurable LPL activity, nevertheless dramatically lowered their elevated plasma TG levels indicates that apoC-III lowers TGs in a non-LPL-dependent manner (40.Gaudet D. Brisson D. Tremblay K. Alexander V.J. Singleton W. Hughes S.G. Geary R.S. Baker B.F. Graham M.J. Crooke R.M. et al.Targeting APOC3 in the familial chylomicronemia syndrome.N. Engl. J. Med. 2014; 371: 2200-2206Crossref PubMed Scopus (337) Google Scholar). This now appears to be inhibition by apoC-III of receptor-mediated hepatic clearance of TG-rich lipoproteins (41.Gordts P.L. Nock R. Son N.H. Ramms B. Lew I. Gonzales J.C. Thacker B.E. Basu D. Lee R.G. Mullick A.E. et al.ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors.J. Clin. Invest. 2016; (Epub ahead of print. July 11, 2016; doi:10.1172/JCI86610.)Crossref PubMed Scopus (156) Google Scholar). Whether interfering with apoC-III production or activity could prevent CHD in individuals with milder TG elevations remains to be proven. apoA-V, encoded by the APOA5 gene, is an exchangeable apolipoprotein discovered bioinformatically (42.Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Crossref PubMed Scopus (800) Google Scholar), that has a central role in metabolism of TG-rich lipoproteins (43.Forte T.M. Sharma V. Ryan R.O. Apolipoprotein A-V gene therapy for disease prevention / treatment: a critical analysis.J. Biomed. Res. 2016; 30: 88-93PubMed Google Scholar). Some liver-derived apoA-V is secreted into plasma and facilitates LPL-mediated TG hydrolysis, while another portion is recoverable intracellularly, in association with cytosolic lipid droplets (43.Forte T.M. Sharma V. Ryan R.O. Apolipoprotein A-V gene therapy for disease prevention / treatment: a critical analysis.J. Biomed. Res. 2016; 30: 88-93PubMed Google Scholar). Loss of apoA-V function is positively correlated with elevated plasma TG and increased CHD risk (44.Do R. Stitziel N.O. Won H.H. Jorgensen A.B. Duga S. Angelica Merlini P. Kiezun A. Farrall M. Goel A. Zuk O. et al.Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.Nature. 2015; 518: 102-106Crossref PubMed Scopus (484) Google Scholar, 45.Teslovich T.M. Musunuru K. Smith A.V. Edmondson A.C. Stylianou I.M. Koseki M. Pirruccello J.P. Ripatti S. Chasman D.I. Willer C.J. et al.Biological, clinic" @default.
• W2475024711 created "2016-07-22" @default.
• W2475024711 creator A5035358062 @default.
• W2475024711 date "2016-09-01" @default.
• W2475024711 modified "2023-10-12" @default.
• W2475024711 title "Multidimensional regulation of lipoprotein lipase: impact on biochemical and cardiovascular phenotypes" @default.
• W2475024711 cites W1527680278 @default.
• W2475024711 cites W1841798962 @default.
• W2475024711 cites W1940633069 @default.
• W2475024711 cites W1963872182 @default.
• W2475024711 cites W1973309410 @default.
• W2475024711 cites W1980683491 @default.
• W2475024711 cites W1987372898 @default.
• W2475024711 cites W2001609219 @default.
• W2475024711 cites W2003283414 @default.
• W2475024711 cites W2015836295 @default.
• W2475024711 cites W2022332493 @default.
• W2475024711 cites W2023466812 @default.
• W2475024711 cites W2031053394 @default.
• W2475024711 cites W2031857626 @default.
• W2475024711 cites W2032456325 @default.
• W2475024711 cites W2033886436 @default.
• W2475024711 cites W2037407219 @default.
• W2475024711 cites W2041953515 @default.
• W2475024711 cites W2046021087 @default.
• W2475024711 cites W2049135972 @default.
• W2475024711 cites W2050838276 @default.
• W2475024711 cites W2052644460 @default.
• W2475024711 cites W2055710516 @default.
• W2475024711 cites W2058804806 @default.
• W2475024711 cites W2060592444 @default.
• W2475024711 cites W2061100095 @default.
• W2475024711 cites W2067802636 @default.
• W2475024711 cites W2068700927 @default.
• W2475024711 cites W2070824641 @default.
• W2475024711 cites W2071157052 @default.
• W2475024711 cites W2097893773 @default.
• W2475024711 cites W2103504539 @default.
• W2475024711 cites W2106937178 @default.
• W2475024711 cites W2109333627 @default.
• W2475024711 cites W2115509231 @default.
• W2475024711 cites W2115801316 @default.
• W2475024711 cites W2125355462 @default.
• W2475024711 cites W2127958304 @default.
• W2475024711 cites W2133407565 @default.
• W2475024711 cites W2141428393 @default.
• W2475024711 cites W2144516660 @default.
• W2475024711 cites W2146750742 @default.
• W2475024711 cites W2149813409 @default.
• W2475024711 cites W2150874658 @default.
• W2475024711 cites W2154326493 @default.
• W2475024711 cites W2170009139 @default.
• W2475024711 cites W2208402374 @default.
• W2475024711 cites W2209861769 @default.
• W2475024711 cites W2275234007 @default.
• W2475024711 cites W2294822677 @default.
• W2475024711 cites W2315899065 @default.
• W2475024711 cites W2317368319 @default.
• W2475024711 cites W2317886503 @default.
• W2475024711 cites W2323589075 @default.
• W2475024711 cites W2327038295 @default.
• W2475024711 cites W2331756138 @default.
• W2475024711 cites W2334579686 @default.
• W2475024711 cites W2345410714 @default.
• W2475024711 cites W2471143596 @default.
• W2475024711 doi "https://doi.org/10.1194/jlr.c070946" @default.
• W2475024711 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5003155" @default.
• W2475024711 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/27412676" @default.
• W2475024711 hasPublicationYear "2016" @default.
• W2475024711 type Work @default.
• W2475024711 sameAs 2475024711 @default.
• W2475024711 citedByCount "18" @default.
• W2475024711 countsByYear W24750247112017 @default.
• W2475024711 countsByYear W24750247112018 @default.
• W2475024711 countsByYear W24750247112019 @default.
• W2475024711 countsByYear W24750247112020 @default.
• W2475024711 countsByYear W24750247112021 @default.
• W2475024711 countsByYear W24750247112022 @default.
• W2475024711 crossrefType "journal-article" @default.
• W2475024711 hasAuthorship W2475024711A5035358062 @default.
• W2475024711 hasBestOaLocation W24750247111 @default.
• W2475024711 hasConcept C104317684 @default.
• W2475024711 hasConcept C127716648 @default.
• W2475024711 hasConcept C181199279 @default.
• W2475024711 hasConcept C185592680 @default.
• W2475024711 hasConcept C2778163477 @default.
• W2475024711 hasConcept C2779697368 @default.
• W2475024711 hasConcept C2780072125 @default.
• W2475024711 hasConcept C55493867 @default.
• W2475024711 hasConcept C86803240 @default.
• W2475024711 hasConcept C94879076 @default.
• W2475024711 hasConceptScore W2475024711C104317684 @default.
• W2475024711 hasConceptScore W2475024711C127716648 @default.
• W2475024711 hasConceptScore W2475024711C181199279 @default.
• W2475024711 hasConceptScore W2475024711C185592680 @default.
• W2475024711 hasConceptScore W2475024711C2778163477 @default.
• W2475024711 hasConceptScore W2475024711C2779697368 @default.
• W2475024711 hasConceptScore W2475024711C2780072125 @default.

• next