Disruption of the murine procollagen C-proteinase enhancer 2 gene causes accumulation of pro-apoA-I and increased HDL levels

Abstract

Given the increased prevalence of cardiovascular disease in the world, the search for genetic variations that impact risk factors associated with the development of this disease continues. Multiple genetic association studies demonstrate that procollagen C-proteinase enhancer 2 (PCPE2) modulates HDL levels. Recent studies revealed an unexpected role for this protein in the proteolytic processing of pro-apolipoprotein (apo) A-I by enhancing the cleavage of the hexapeptide extension present at the N-terminus of apoA-I. To investigate the role of the PCPE2 protein in an in vivo model, PCPE2-deficient (PCPE2 KO) mice were examined, and a detailed characterization of plasma lipid profiles, apoA-I, HDL speciation, and function was done. Results of isoelectric focusing (IEF) electrophoresis together with the identification of the amino terminal peptides DEPQSQWDK and WHVWQQDEPQSQWDVK, representing mature apoA-I and pro-apoA-I, respectively, in serum from PCPE2 KO mice confirmed that PCPE2 has a role in apoA-I maturation. Lipid profiles showed a marked increase in plasma apoA-I and HDL-cholesterol (HDL-C) levels in PCPE2 KO mice compared with wild-type littermates, regardless of gender or diet. Changes in HDL particle size and electrophoretic mobility observed in PCPE2 KO mice suggest that the presence of pro-apoA-I impairs the maturation of HDL. ABCA1-dependent cholesterol efflux is defective in PCPE2 KO mice, suggesting that the functionality of HDL is altered. Given the increased prevalence of cardiovascular disease in the world, the search for genetic variations that impact risk factors associated with the development of this disease continues. Multiple genetic association studies demonstrate that procollagen C-proteinase enhancer 2 (PCPE2) modulates HDL levels. Recent studies revealed an unexpected role for this protein in the proteolytic processing of pro-apolipoprotein (apo) A-I by enhancing the cleavage of the hexapeptide extension present at the N-terminus of apoA-I. To investigate the role of the PCPE2 protein in an in vivo model, PCPE2-deficient (PCPE2 KO) mice were examined, and a detailed characterization of plasma lipid profiles, apoA-I, HDL speciation, and function was done. Results of isoelectric focusing (IEF) electrophoresis together with the identification of the amino terminal peptides DEPQSQWDK and WHVWQQDEPQSQWDVK, representing mature apoA-I and pro-apoA-I, respectively, in serum from PCPE2 KO mice confirmed that PCPE2 has a role in apoA-I maturation. Lipid profiles showed a marked increase in plasma apoA-I and HDL-cholesterol (HDL-C) levels in PCPE2 KO mice compared with wild-type littermates, regardless of gender or diet. Changes in HDL particle size and electrophoretic mobility observed in PCPE2 KO mice suggest that the presence of pro-apoA-I impairs the maturation of HDL. ABCA1-dependent cholesterol efflux is defective in PCPE2 KO mice, suggesting that the functionality of HDL is altered. Cubbing in proapolipoprotein maturationJournal of Lipid ResearchVol. 52Issue 11PreviewIn this issue of the Journal of Lipid Research, Francone and colleagues have described an interesting HDL phenotype in a mouse deficient in procollagen proteinase enhancer 2 (PCPE2). Present in the plasma of the mice are preβ HDL containing as its major, if not only, apolipoprotein pro-apoA-I, accompanied by the accumulation of an enlarged HDL also containing predominantly pro-apoA-I. This highlights a potentially new actor in the regulation of HDL homeostasis. Recent genetic association studies have suggested that PCPE2 variation may be weakly associated with HDL levels (1). Full-Text PDF Open Access Epidemiological studies from the past five decades have consistently shown that levels of HDL-cholesterol (HDL-C) are inversely correlated with clinical events resulting from atherosclerosis (1Robins S.J. Collins D. Wittes J.T. Papademetriou V. Deedwania P.C. Schaefer E.J. McNamara J.R. Kashyap M.L. Hershman J.M. Wexler L.F. et al.Relation of gemfibrozil treatment and lipid levels with major coronary events. VA-HIT: a randomized controlled trial.JAMA. 2001; 285: 1585-1591Crossref PubMed Scopus (851) Google Scholar, 2Manninen V. Elo M.O. Frick M.H. Haapa K. Heinonen O.P. Heinsalmi P. Helo P. Huttunen J.K. Kaitaniemi P. Koskinen P. et al.Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study.JAMA. 1988; 260: 641-651Crossref PubMed Scopus (856) Google Scholar), whereas LDL-cholesterol (LDL-C) levels are directly related to the incidence of these events. HDL protects against cardiovascular disease by regulating cholesterol efflux from peripheral tissues and modulating inflammation (3Tall A.R. Yvan-Charvet L. Terasaka N. Pagler T. Wang N. ABC transporters and cholesterol efflux: implications for the treatment of atherosclerosis.Cell Metab. 2008; 7: 365-375Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar). Other anti-atherogenic properties of HDL include its antioxidant and vasoprotective properties (4Navab M. Reddy S.T. Van Lenten B.J. Fogelman A.M. HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms.Nat. Rev. Cardiol. 2011; 8: 222-232Crossref PubMed Scopus (467) Google Scholar). The importance of HDL in disease together with the accuracy with which it can be measured in plasma specimens makes it amenable for genetic studies. Twin studies have indicated that 50% of the variation in HDL-C levels is genetically determined (5Goode E.L. Cherny S.S. Christian J.C. Jarvik G.P. de Andrade M. Heritability of longitudinal measures of body mass index and lipid and lipoprotein levels in aging twins.Twin Res. Hum. Genet. 2007; 10: 703-711Crossref PubMed Scopus (60) Google Scholar) and that at least 50 different genes are reported to be associated with HDL-C. Large population studies (6Spirin V. Schmidt S. Pertsemlidis A. Cooper R.S. Cohen J.C. Sunyaev S.R. Common single-nucleotide polymorphisms act in concert to affect plasma levels of high-density lipoprotein cholesterol.Am. J. Hum. Genet. 2007; 81: 1298-1303Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 7Teslovich 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, clinical, and population relevance of 95 loci for blood lipids.Nature. 2010; 466: 707-713Crossref PubMed Scopus (2827) Google Scholar, 8Willer C.J. Sanna S. Jackson A.U. Scuteri A. Bonnycastle L.L. Clarke R. Heath S.C. Timpson N.J. Najjar S.S. Stringhman H.M. et al.Newly identified loci that influence lipid concentrations and risk of coronary artery disease.Nat. Genet. 2008; 40: 161-169Crossref PubMed Scopus (1330) Google Scholar) have identified single-nucleotide polymorphisms at multiple loci associated with various HDL-cholesterol levels. Recently, studies have started to address the extent to which genetics impacts HDL. However, the genetic component of variation of HDL-C is not fully by that genes that have or that are in of these the genetic may be to be to impact HDL-C or to the of genes with an as and relevance are that genes are in the of HDL-C and cardiovascular disease studies by genetic is procollagen C-proteinase and as and of a procollagen C-proteinase enhancer protein from the PubMed Scopus Google Scholar). PCPE2 was to be associated with HDL in population P. of to for association with HDL cholesterol PubMed Scopus Google Scholar, J. J. J.P. Francone of processing by procollagen C-proteinase and Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). PCPE2 was identified by and of a procollagen C-proteinase enhancer protein from the PubMed Scopus Google Scholar) in the in an to the for were and PCPE2 is as the its function a protein of amino to the procollagen C-proteinase enhancer protein a procollagen C-proteinase enhancer (PCPE2) that is a protein in of and from the described Full Text Full Text PDF PubMed Scopus Google Scholar). and PCPE2 are that can the processing of by as of and in studies have the role of T. S. L. S. of procollagen C-proteinase to and role in with 2010; 285: Full Text Full Text PDF PubMed Scopus (32) Google Scholar, M. D. S. A. et of the of procollagen C-proteinase in the of 2010; 285: Full Text Full Text PDF PubMed Scopus Google Scholar), the function of PCPE2 PCPE2-deficient (PCPE2 KO) mice are and and not K. The and are not for J. 2007; PubMed Scopus Google Scholar). a of P. of to for association with HDL cholesterol PubMed Scopus Google Scholar) in PCPE2 an role for this protein in apoA-I and HDL was with the to HDL levels observed in genetic PCPE2 is present and HDL in plasma from of and confirmed this by that PCPE2 in the regulation of apoA-I by the proteolytic processing of pro-apolipoprotein A-I by P. C.J. proapolipoprotein and its for lipid 2007; PubMed Scopus Google Scholar). and studies that PCPE2 with and pro-apoA-I to a and the cleavage of the hexapeptide extension present at the N-terminus of apoA-I. an to the role of PCPE2 HDL and the suggested by in PCPE2 KO mice and the of PCPE2 plasma apoA-I, and HDL properties and The PCPE2 mice were K. 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To the lipid of wild-type and PCPE2 KO to HDL were and and and cholesterol were determined by the of the major lipid was not was a increase in apoA-I in HDL from PCPE2 KO mice The increased apoA-I in PCPE2 KO mice to of the HDL that was a in the of and maturation of HDL in PCPE2 KO an the apoA-I to cholesterol is increased in PCPE2 KO compared with wild-type and for PCPE2 KO and wild-type mice, to was not suggesting that the of plasma cholesterol was not in PCPE2 KO mice not lipid in wild-type and PCPE2 KO of plasma from and PCPE2 KO mice were to HDL by as described in containing the HDL lipoprotein were and cholesterol and apoA-I were determined as described in and apoA-I are in in is the to the of and Open in a new of plasma from and PCPE2 KO mice were to HDL by as described in containing the HDL lipoprotein were and cholesterol and apoA-I were determined as described in and apoA-I are in in is the to the of and characterization of HDL in PCPE2 KO mice was by which HDL by and HDL was an HDL was not different wild-type and PCPE2 KO mice the of was wild-type HDL. apoA-I, which its by these suggest that the increased presence of pro-apoA-I in PCPE2 KO mice the properties of these with this of HDL by electrophoresis identified a HDL the size compared with wild-type Changes in HDL were also plasma from wild-type and PCPE2 KO mice were by shown in was an increased of present in a HDL This population of HDL observed in PCPE2 KO mice may have apoA-I and may have at least in for the increased apoA-I levels observed in plasma from of were to the in HDL size and properties observed in PCPE2 KO mice have an impact the of HDL to cholesterol in and of were from plasma by and the containing HDL were with to the described in the of cholesterol and of was increased by HDL from PCPE2 KO mice the of cholesterol not in apoA-I and HDL-C observed in PCPE2 KO mice, suggesting that HDL from PCPE2 KO mice is not as as wild-type HDL in cholesterol from To address these cholesterol and were to the apoA-I and HDL-C levels in the mouse which are of HDL function and efflux shown in to the serum of apoA-I in a and in the of cholesterol from with PCPE2 KO HDL. The in of cholesterol to HDL from PCPE2 KO compared with wild-type HDL was by the in the efflux of cholesterol the were observed the of cholesterol in and of was to levels of cholesterol present in the HDL not The serum of apoA-I be as an of the of HDL the shown in indicated HDL in serum from KO mice a to cholesterol to serum apoA-I and HDL-C of to serum shown in were to the serum of apoA-I The concentrations in serum from wild-type mice were apoA-I and HDL-C The concentrations in serum from PCPE2 KO mice were apoA-I and HDL-C was by Large an to the in the of PCPE2 KO mice HDL to efflux cholesterol from an was to and efflux as as the cholesterol efflux shown in and in efflux of cholesterol by or were observed PCPE2 KO mouse HDL was the to apoA-I HDL from PCPE2 KO mice showed a in the to efflux cholesterol the these suggest in the of the population of HDL in serum are in efflux resulting in a of cholesterol is the major protein component of HDL. The and are the of in and and proapolipoprotein A-I which is to apolipoprotein A-I in the Full Text PDF PubMed Google Scholar, and regulation of apolipoprotein Full Text PDF PubMed Google Scholar). as an with a hexapeptide extension at its amino and processing of apolipoprotein apolipoprotein A-I is a PubMed Scopus Google Scholar). processing of pro-apoA-I to apoA-I in and plasma P. C.J. proapolipoprotein and its for lipid 2007; PubMed Scopus Google Scholar). of the hexapeptide to amino the mature amino protein for the and of HDL A. M. of and in the of PubMed Scopus Google Scholar). the major apolipoprotein of is also and as pro-apolipoprotein and processing of of Lipid Res. Full Text PDF PubMed Google Scholar). in a of in to is in the of apoA-I procollagen C-proteinase (PCPE2) P. of to for association with HDL cholesterol PubMed Scopus Google Scholar). and studies have the of the of apoA-I, and to pro-apoA-I by PCPE2 the which the of cleavage and the of mature apoA-I P. of to for association with HDL cholesterol PubMed Scopus Google Scholar). and PCPE2 in and mice are The association genetic polymorphisms the PCPE2 and HDL levels and of a procollagen C-proteinase enhancer protein from the PubMed Scopus Google Scholar, P. of to for association with HDL cholesterol PubMed Scopus Google Scholar) together with studies P. of to for association with HDL cholesterol PubMed Scopus Google Scholar) for a role of PCPE2 in plasma HDL as are to in or apoA-I in the of pro-apoA-I containing a hexapeptide extension at the that is suggesting that a described for in the hexapeptide extension and cleavage is to that in with the of the at in of an in the and a a at the N. A. K. of the mouse apolipoprotein and protein with to PubMed Scopus Google Scholar). The from PCPE2 KO mice the role of PCPE2 in the processing of pro-apoA-I. levels of pro-apoA-I were observed in the plasma of wild-type mice, the presence of the containing the in apoA-I from PCPE2 KO mice that in mice, PCPE2 in the processing and maturation of apoA-I. not the of pro-apoA-I in the plasma of PCPE2 KO mice are the of the peptides from mature and pro-apoA-I by mass are as are not by also by of suggest that a of the apoA-I in plasma of mice deficient in PCPE2 was present as a compared with wild-type electrophoresis of apoA-I from wild-type and PCPE2 KO mice showed a in the isoelectric the presence of a of apoA-I in the PCPE2 KO and identification of amino terminal peptides by mass the presence of pro-apoA-I in PCPE2 KO the electrophoretic of PCPE2 KO in was present in wild-type mouse apoA-I C.J. of cholesterol high-density 1988; PubMed Scopus Google Scholar), these were with the increase in in pro-apoA-I at of apoA-I electrophoresis of plasma HDL showed the presence of apoA-I and with the properties of wild-type suggesting that the of apoA-I present in PCPE2 KO mice was in the it is also that the presence of pro-apoA-I in was to the properties of wild-type in PCPE2 KO mice the polymorphisms in the PCPE2 and HDL levels. of C.J. Sanna S. Jackson A.U. Scuteri A. Bonnycastle L.L. Clarke R. Heath S.C. Timpson N.J. Najjar S.S. Stringhman H.M. et al.Newly identified loci that influence lipid concentrations and risk of coronary artery disease.Nat. Genet. 2008; 40: 161-169Crossref PubMed Scopus (1330) Google Scholar, and of a procollagen C-proteinase enhancer protein from the PubMed Scopus Google Scholar), a and association polymorphisms and and of the PCPE2 and HDL levels was is to that a association of polymorphisms and HDL levels is for a genes with or in M. The of HDL 2008; PubMed Scopus Google Scholar). is the for the of the of for the treatment of cardiovascular and association with and and for to in Genet. PubMed Scopus Google Scholar, D.I. D. L. of and cholesterol PubMed Scopus Google Scholar, M. P. J. et association of in genes with J. PubMed Scopus Google Scholar, Smith Wang D. 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Genet. 2008; 40: 161-169Crossref PubMed Scopus (1330) Google Scholar). a of the of these A. N. A. et of lipid J. Hum. Genet. 2011; PubMed Scopus Google Scholar). studies together with the of the PCPE2 KO mice in of an association PCPE2 and plasma HDL the for and studies to and relevance to genetic observed in genes with function and the anti-atherogenic role of HDL has and for it has that HDL is in its lipid and protein The and anti-atherogenic properties of Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, lipoprotein and function in cholesterol 2010; PubMed Scopus Google Scholar), to multiple with different and A.V. M. de M. A. K. M.L. et efflux high-density lipoprotein and J. 2011; PubMed Scopus Google Scholar), an association HDL-C efflux and has suggesting that cholesterol efflux can a as a clinical for HDL studies PCPE2 KO mice demonstrate that in apoA-I processing and maturation the of HDL to efflux studies that the of cholesterol from was not increased in PCPE2 KO mice, the marked increase in plasma apoA-I and HDL-C levels. of the various in cholesterol efflux a in the to efflux cholesterol the the is for the efflux of cholesterol and of apoA-I to the of these suggest that the presence of pro-apoA-I the of to efflux The properties of pro-apoA-I as the that in vivo apoA-I and mature HDL. studies have shown that pro-apoA-I is with lipid properties A. and characterization of proapolipoprotein Lipid Res. Full Text PDF PubMed Google Scholar), A. A. M. T. D. N. J. lipid associated with to plasma 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), and cholesterol efflux to for mature apoA-I, P. 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HDL from PCPE2 KO mouse plasma be to the impact and the the presence of the in pro-apoA-I the with and of apoA-I. these the that the functionality of HDL may be its levels. studies have to be to these have an impact the development of The for the increased plasma levels of apoA-I and HDL-C observed in PCPE2 KO mice is of in the of apoA-I in and of PCPE2 KO mice suggest that the increase in apoA-I is not to in the of apoA-I. in the levels of or were observed in and from PCPE2 KO The in particle shown in PCPE2 KO mice, together with the presence of a HDL shown by electrophoresis suggest that the of HDL be altered. the increase in and apoA-I at least in an increase in the of apoA-I in PCPE2 KO mouse HDL compared with wild-type Changes in the of apoA-I HDL particle have observed in apoA-I mice and have associated with an increased particle size and resulting in the of HDL in the plasma studies have to be in to address a is for the accumulation of HDL in PCPE2 KO in the of also to the increased levels of apoA-I and HDL-C observed in PCPE2 KO the from these studies a new in the regulation of apoA-I The of genetic association J. J. J.P. Francone of processing by procollagen C-proteinase and Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar), and characterization of PCPE2 KO mice a role for a with role in This have to be in the to from genetic or genes with cholesterol HDL-cholesterol isoelectric focusing LDL-cholesterol multiple procollagen C-proteinase enhancer 2 isoelectric cholesterol wild-type