Obesity and altered glucose metabolism impact HDL composition in CETP transgenic mice: a role for ovarian hormones

Mechanisms underlying changes in HDL composition caused by obesity are poorly defined, partly because mice lack expression of cholesteryl ester transfer protein (CETP), which shuttles triglyceride and cholesteryl ester between lipoproteins. Because menopause is associated with weight gain, altered glucose metabolism, and changes in HDL, we tested the effect of feeding a high-fat diet (HFD) and ovariectomy (OVX) on glucose metabolism and HDL composition in CETP transgenic mice. After OVX, female CETP-expressing mice had accelerated weight gain with HFD-feeding and impaired glucose tolerance by hyperglycemic clamp techniques, compared with OVX mice fed a low-fat diet (LFD). Sham-operated mice (SHAM) did not show HFD-induced weight gain and had less glucose intolerance than OVX mice. Using shotgun HDL proteomics, HFD-feeding in OVX mice had a large effect on HDL composition, including increased levels of apoA2, apoA4, apoC2, and apoC3, proteins involved in TG metabolism. These changes were associated with decreased hepatic expression of SR-B1, ABCA1, and LDL receptor, proteins involved in modulating the lipid content of HDL. In SHAM mice, there were minimal changes in HDL composition with HFD feeding. These studies suggest that the absence of ovarian hormones negatively influences the response to high-fat feeding in terms of glucose tolerance and HDL composition. CETP-expressing mice may represent a useful model to define how metabolic changes affect HDL composition and function. Mechanisms underlying changes in HDL composition caused by obesity are poorly defined, partly because mice lack expression of cholesteryl ester transfer protein (CETP), which shuttles triglyceride and cholesteryl ester between lipoproteins. Because menopause is associated with weight gain, altered glucose metabolism, and changes in HDL, we tested the effect of feeding a high-fat diet (HFD) and ovariectomy (OVX) on glucose metabolism and HDL composition in CETP transgenic mice. After OVX, female CETP-expressing mice had accelerated weight gain with HFD-feeding and impaired glucose tolerance by hyperglycemic clamp techniques, compared with OVX mice fed a low-fat diet (LFD). Sham-operated mice (SHAM) did not show HFD-induced weight gain and had less glucose intolerance than OVX mice. Using shotgun HDL proteomics, HFD-feeding in OVX mice had a large effect on HDL composition, including increased levels of apoA2, apoA4, apoC2, and apoC3, proteins involved in TG metabolism. These changes were associated with decreased hepatic expression of SR-B1, ABCA1, and LDL receptor, proteins involved in modulating the lipid content of HDL. In SHAM mice, there were minimal changes in HDL composition with HFD feeding. These studies suggest that the absence of ovarian hormones negatively influences the response to high-fat feeding in terms of glucose tolerance and HDL composition. CETP-expressing mice may represent a useful model to define how metabolic changes affect HDL composition and function. Impairment in HDL function associated with obesity and elevated serum triglyceride (TG) may be a major contributor to risk of coronary heart disease (CHD) in obese patients, yet mechanisms by which changes in metabolism impair HDL function are not well defined (1Lamarche B. Uffelman K.D. Carpentier A. Cohn J.S. Steiner G. Barrett P.H. Lewis G.F. Triglyceride enrichment of HDL enhances in vivo metabolic clearance of HDL apo A-I in healthy men.J. Clin. Invest. 1999; 103: 1191-1199Crossref PubMed Scopus (207) Google Scholar, 2Lewis G.F. Uffelman K.D. Szeto L.W. Weller B. Steiner G. Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans.J. Clin. Invest. 1995; 95: 158-166Crossref PubMed Google Scholar, 3Horowitz B.S. Goldberg I.J. Merab J. Vanni T.M. Ramakrishnan R. Ginsberg H.N. Increased plasma and renal clearance of an exchangeable pool of apolipoprotein A-I in subjects with low levels of high density lipoprotein cholesterol.J. Clin. Invest. 1993; 91: 1743-1752Crossref PubMed Scopus (192) Google Scholar, 4Van Lenten B.J. Hama S.Y. de Beer F.C. Stafforini D.M. McIntyre T.M. Prescott S.M. La Du B.N. Fogelman A.M. Navab M. Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response: loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures.J. Clin. Invest. 1995; 96: 2758-2767Crossref PubMed Scopus (705) Google Scholar, 5Eckel R.H. Barouch W.W. Ershow A.G. Report of the National Heart, Lung, and Blood Institute-National Institute of Diabetes and Digestive and Kidney Diseases Working Group on the pathophysiology of obesity-associated cardiovascular disease.Circulation. 2002; 105: 2923-2928Crossref PubMed Scopus (199) Google Scholar–6Goldberg I.J. Eckel R.H. McPherson R. Triglycerides and heart disease: still a hypothesis?.Arterioscler. Thromb. Vasc. Biol. 2011; 31: 1716-1725Crossref PubMed Scopus (158) Google Scholar). Increased TGs in the form of VLDL give rise to low levels of HDL in part due to the actions of cholesteryl ester transfer protein (CETP), which shuttles TG and cholesteryl esters between serum lipoproteins. Because of lipid exchange, elevated serum VLDL leads to TG enrichment of HDL. This TG enrichment reduces the affinity of apolipoprotein A1 (apoA1) for cholesterol, promotes clearance of apoA1, and decreases HDL particle number (1Lamarche B. Uffelman K.D. Carpentier A. Cohn J.S. Steiner G. Barrett P.H. Lewis G.F. Triglyceride enrichment of HDL enhances in vivo metabolic clearance of HDL apo A-I in healthy men.J. Clin. Invest. 1999; 103: 1191-1199Crossref PubMed Scopus (207) Google Scholar, 3Horowitz B.S. Goldberg I.J. Merab J. Vanni T.M. Ramakrishnan R. Ginsberg H.N. Increased plasma and renal clearance of an exchangeable pool of apolipoprotein A-I in subjects with low levels of high density lipoprotein cholesterol.J. Clin. Invest. 1993; 91: 1743-1752Crossref PubMed Scopus (192) Google Scholar, 7Brinton E.A. Eisenberg S. Breslow J.L. Elevated high density lipoprotein cholesterol levels correlate with decreased apolipoprotein A-I and A-II fractional catabolic rate in women.J. Clin. Invest. 1989; 84: 262-269Crossref PubMed Scopus (124) Google Scholar). In addition, changes in the function of HDL related to inflammation, coagulation, and reverse cholesterol transport are associated with obesity and metabolic diseases. HDL proteomics have revealed changes in apolipoproteins, inflammatory proteins, and coagulation proteins in individuals with known CHD compared with control subjects (8Collins L.A. Olivier M. Quantitative comparison of lipoprotein fractions derived from human plasma and serum by liquid chromatography-tandem mass spectrometry.Proteome Sci. 2010; 8: 42Crossref PubMed Scopus (16) Google Scholar, 9Julve J. Escola-Gil J.C. Rotllan N. Fievet C. Vallez E. de la Torre C. Ribas V. Sloan J.H. Blanco-Vaca F. Human apolipoprotein A-II determines plasma triglycerides by regulating lipoprotein lipase activity and high-density lipoprotein proteome.Arterioscler. Thromb. Vasc. Biol. 2010; 30: 232-238Crossref PubMed Scopus (62) Google Scholar, 10Davidsson P. Hulthe J. Fagerberg B. Camejo G. Proteomics of apolipoproteins and associated proteins from plasma high-density lipoproteins.Arterioscler. Thromb. Vasc. Biol. 2010; 30: 156-163Crossref PubMed Scopus (71) Google Scholar, 11Stahlman M. Davidsson P. Kanmert I. Rosengren B. Boren J. Fagerberg B. Camejo G. Proteomics and lipids of lipoproteins isolated at low salt concentrations in D2O/sucrose in PubMed Scopus Google S. J. S. S. P. proteomics and in the of Clin. Invest. PubMed Scopus Google Scholar). These of HDL are known to CHD risk of HDL cholesterol levels Lenten B.J. Hama S.Y. de Beer F.C. Stafforini D.M. McIntyre T.M. Prescott S.M. La Du B.N. Fogelman A.M. Navab M. Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response: loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures.J. Clin. Invest. 1995; 96: 2758-2767Crossref PubMed Scopus (705) Google Scholar, M. Hama S.Y. G. Fogelman A.M. for HDL that is in the of PubMed Google Scholar, G.F. the of HDL metabolism and reverse cholesterol 96: PubMed Scopus Google Scholar, S. lipoprotein and cardiovascular Clin. 2010; PubMed Scopus Google Scholar, M. de la M. A. high-density lipoprotein and J. 2011; PubMed Scopus Google C. acute phase response reverse cholesterol 2010; PubMed Scopus Google Scholar). due to the of cardiovascular disease in is how acute changes in metabolism in changes in HDL composition. In menopause a in cardiovascular risk associated with glucose metabolism, and by increased and decreased HDL B. S. during of and J. PubMed Scopus Google Scholar, F. E. B.S. S. B. menopause not in lipoprotein metabolism Clin. 2010; 95: PubMed Scopus Google not insulin J. Google Scholar). of obesity and impaired glucose the of changes on HDL composition to partly because the model of metabolic the CETP CETP transgenic mice a lipid with elevated VLDL and LDL and decreased HDL and are an model of A. A. Breslow J.L. of hepatic cholesteryl ester transfer protein expression in apolipoprotein and low density lipoprotein a changes in plasma cholesterol Clin. Invest. PubMed Scopus Google Scholar, in transgenic mice cholesteryl ester transfer 1993; PubMed Scopus Google A. Breslow J.L. A. cholesterol of the human cholesteryl ester transfer protein in transgenic on Clin. Invest. PubMed Google Scholar). of HDL in CETP mice, and to HDL composition in is not that we CETP-expressing mice to define how metabolic changes associated with obesity affect HDL composition. to define how in glucose and TG metabolism associated with obesity affect HDL composition. ovariectomy (OVX) a model of menopause because OVX mice are to obesity and in glucose and TG metabolism. of CETP-expressing mice have to the of CETP expression on lipid metabolism. In and in mice the human CETP CETP expression is with is by acute and is by ovarian hormones A. Breslow J.L. A. cholesterol of the human cholesteryl ester transfer protein in transgenic on Clin. Invest. PubMed Google Scholar, ester transfer protein expression is in transgenic PubMed Scopus Google Scholar, S. N. S. S. M. E. plasma cholesteryl ester transfer protein in obese a for the of serum HDL cholesterol levels in Thromb. PubMed Google F. B.S. B. lipid transfer in and obese and PubMed Scopus Google Scholar). mice that the CETP in transgenic mice cholesteryl ester transfer 1993; PubMed Scopus Google Scholar, of cholesteryl ester transfer protein in apolipoprotein A-I from studies with transgenic Thromb. PubMed Google to define how metabolic changes affect HDL composition, of in CETP define metabolic that related to in HDL composition, we hyperglycemic clamp to define glucose tolerance in vivo the of glucose changes and changes in serum insulin that from glucose hyperglycemic clamp to a in glucose levels between and define the effect of HFD feeding and OVX on glucose tolerance and the insulin shotgun proteomics of HDL to define changes in HDL proteins HFD feeding and HFD feeding had a effect on glucose tolerance and HDL composition These studies suggest a of obesity and HFD feeding on HDL protein composition the loss of ovarian CETP transgenic mice on a number were from mice were on a diet on a from a HFD from are from and the from were in with National of for the and of and were by the and at mice were on with the between the of the and to the and the were the by the and were and with in an and the and SHAM were the by the and the and After mice were to on a a HFD for in mice have by S. for and metabolic of glucose in 2010; PubMed Scopus Google Scholar). 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PubMed Scopus (192) Google Scholar). from on a and fractions were in a content from the fractions a from VLDL fractions were defined fractions LDL fractions and HDL fractions of and for TG and cholesterol levels and of for CETP activity to the were between were by by by by protein from fractions that to HDL from mice from were by protein and mass of the by protein PubMed Scopus Google Scholar). of HDL were in of and at and the were with and with After with to of and to the proteins at were by A. R. M. A. of protein from protein and Sci. 2002; PubMed Scopus Google Scholar, J. D.M. E. of protein mass 1999; PubMed Scopus Google Scholar). were a cell a an This with of by of with a on an mass with an an and a were of in and salt by a phase from in to in mass were the a of by of of the a the response from HDL of mice, we for the were to by the M. R. 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HFD-feeding did not weight gain in SHAM mice an of insulin we glucose and insulin were in glucose between HFD feeding in the SHAM and OVX associated with a elevated insulin and were in CETP activity between because mice the CETP These suggest that the of ovarian hormones against obesity not insulin on elevated serum insulin in weight high-fat feeding in CETP mice OVX a to weight gain associated with menopause changes in CETP activity in glucose metabolism menopause is associated with in serum VLDL and HDL. OVX in impaired glucose metabolism, we hyperglycemic clamp studies in which glucose at This to glucose levels in mice with and of insulin glucose were not between and glucose levels were at a of for of glucose to a of is an of glucose tolerance glucose rate feeding the to in mice and in mice compared with for OVX and for for in the between and mice. mice had the glucose rate of that the absence of ovarian hormones the of HFD feeding on glucose tolerance the clamp we did not insulin This insulin in response to a defined glucose and an of a of glucose HFD feeding to an in serum insulin levels in response to for SHAM and OVX mice compared with control mice with the elevated insulin levels in elevated clamp insulin levels compared with mice that HFD OVX, to that mice had a to mice that OVX insulin OVX to insulin weight gain, HFD feeding OVX weight gain and insulin of ovarian hormones SHAM against weight gain on HFD not insulin with HFD feeding. In insulin serum TG levels by hepatic production of and TG clearance by G.F. Uffelman K.D. Szeto L.W. Weller B. Steiner G. Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans.J. Clin. Invest. 1995; 95: 158-166Crossref PubMed Google Scholar, M. of to in serum very 2010; PubMed Scopus Google Scholar, Eckel R.H. of lipoprotein of the clamp Clin. Invest. PubMed Scopus Google Scholar). of and to serum TG to in obese B. S. during of and J. PubMed Scopus Google Scholar). the of to serum TG we serum TG at and at the of the hyperglycemic clamp studies TG levels were not decreased in response to OVX in the the HFD mice had decreased TG levels the that insulin serum TG ovarian hormones are were in TG levels between serum TG levels were in the during the suggest that loss of ovarian hormones insulin of serum TG levels in CETP mice. serum cholesterol levels were in and mice and mice a in cholesterol compared with mice and lipoproteins by and the cholesterol content of and HDL In mice, VLDL cholesterol there were in HDL cholesterol compared with mice In OVX mice, there a in the cholesterol content of HDL mice did not in HDL cholesterol with HFD feeding compared with feeding OVX did not HDL cholesterol OVX and HFD feeding to altered expression of hepatic proteins involved in lipoprotein we the expression of and expression of HFD-feeding in SHAM and OVX mice were in expression OVX compared with mice. expression of in compared with This diet effect on in OVX there were in the expression of in mice compared with fed mice. the expression of in mice compared with the decreased expression of and are with increased serum cholesterol in mice fed how metabolic changes in glucose and TG metabolism associated with OVX and HFD feeding HDL composition, we a shotgun of HDL. number of proteins in HDL fractions CETP that were by and of proteins for were and the of HDL protein composition, we a to and proteins for In OVX we HDL proteins from HDL that were between and not in HDL from SHAM proteins were to and were to in the OVX there were proteins from HDL fractions that were not in the SHAM proteins were to and were to proteins in are in I. These suggest that OVX a in the of HDL protein composition compared with suggest that HFD feeding a on the of HDL protein composition in OVX mice. defined the of OVX and HFD feeding on HDL composition by of HDL proteins between were HDL proteins between the in of the Using for proteomics, were between to a of of HDL proteins between M. R. P. for proteomics PubMed Scopus Google Scholar, mass by PubMed Scopus Google Scholar, B. and PubMed Scopus Google Scholar, S. S.M. B. protein with high 8: PubMed Scopus Google M. shotgun proteomics and 2010; PubMed Scopus Google Scholar, S. 2010; PubMed Scopus Google Scholar, S. in 2011; PubMed Scopus Google Scholar). for comparison are a of the of proteins compared between the a in known proteins, and a of known HDL proteins that and and show the of which the of HDL a of a in of that protein between major proteins in the HDL of CETP mice and were changes in the protein between of that with in for CETP in HDL were not between by model CETP expression and activity is changes in HDL proteins mice and of the proteins were These proteins involved in and function proteins with known function in HDL, the were in and the of and for proteins with known HDL function for compared with mice. of changes in HDL composition that insulin in SHAM mice and not HDL altered HDL proteins by of the in of HFD feeding in SHAM in lipoprotein the coagulation of HFD feeding in OVX HDL in lipoprotein and and and to the coagulation of OVX in fed HDL and to of OVX in HFD fed HDL phase response: and the coagulation in a HFD feeding in OVX mice in changes in HDL composition because of proteins were compared with HDL from mice These represent proteins involved in coagulation, and lipid metabolism with the of of known HDL proteins in that proteins were by HFD feeding OVX than HFD feeding SHAM in SHAM mice, HFD feeding in OVX mice increased the and content of HDL compared with mice. in and a protein involved in the coagulation and for proteins with known HDL function for mice compared with mice. These changes in HDL proteins the HDL proteins in OVX mice in the in These suggest that HFD feeding a on HDL composition in the absence of ovarian define the of HFD feeding on the mice OVX SHAM define the of OVX on HDL composition compared with we compared HDL from OVX mice with SHAM mice on the In mice, loss of ovarian hormones by OVX associated with changes of the proteins between and were changes in proteins with known HDL function proteins from the define the of OVX on HDL composition in mice on a we compared HDL composition between and mice. In mice, we that OVX associated with protein changes of the proteins between mice increased and suggest that OVX HDL composition on the metabolic HFD feeding. of cardiovascular disease associated with obesity insulin impaired glucose elevated serum low HDL, and loss of protective cardiovascular human HDL proteomics have revealed proteins and have of HDL related to lipid inflammation, coagulation, and (8Collins L.A. Olivier M. Quantitative comparison of lipoprotein fractions derived from human plasma and serum by liquid chromatography-tandem mass spectrometry.Proteome Sci. 2010; 8: 42Crossref PubMed Scopus (16) Google Scholar, 9Julve J. Escola-Gil J.C. Rotllan N. Fievet C. Vallez E. de la Torre C. Ribas V. Sloan J.H. Blanco-Vaca F. Human apolipoprotein A-II determines plasma triglycerides by regulating lipoprotein lipase activity and high-density lipoprotein proteome.Arterioscler. Thromb. Vasc. Biol. 2010; 30: 232-238Crossref PubMed Scopus (62) Google Scholar, 10Davidsson P. Hulthe J. Fagerberg B. Camejo G. Proteomics of apolipoproteins and associated proteins from plasma high-density lipoproteins.Arterioscler. Thromb. Vasc. Biol. 2010; 30: 156-163Crossref PubMed Scopus (71) Google Scholar, 11Stahlman M. Davidsson P. Kanmert I. Rosengren B. Boren J. Fagerberg B. Camejo G. Proteomics and lipids of lipoproteins isolated at low salt concentrations in D2O/sucrose in PubMed Scopus Google S. J. S. S. P. proteomics and in the of Clin. Invest. PubMed Scopus Google Scholar). These studies have that HDL proteins are altered in with that HDL to from CHD and may to an increased risk of mechanisms that metabolic changes with altered HDL composition have because the model of metabolic CETP In we have defined the HDL of female CETP-expressing mice and the of acute metabolic changes by HFD feeding and loss of ovarian that HDL composition in CETP mice is altered by changes in metabolism associated with obesity and that the of HFD feeding on HDL composition is on metabolic CETP-expressing mice were to HFD-induced changes in HDL composition OVX were to changes in HDL composition a the of of in vivo metabolism with HDL proteomics in CETP-expressing mice, we were to metabolic that to changes in HDL composition. a of HFD feeding on of metabolism that to cardiovascular on ovarian CETP mice weight on HFD feeding OVX, CETP mice did absence of weight gain with HFD feeding in the SHAM may be to metabolic caused by CETP In with mice, there a weight gain with of feeding and from weight gain, CETP mice were not from impaired glucose tolerance and insulin with HFD feeding. hyperglycemic clamp we were to at of glucose metabolism that correlate with metabolic glucose and insulin that HFD feeding in SHAM mice to impaired glucose mice in less glucose to than SHAM mice fed of impaired glucose tolerance with HFD feeding with OVX compared with SHAM mice. Because insulin control during we were to insulin a of glucose metabolism. with SHAM mice fed we of the were insulin by in response to a in These that ovarian hormones insulin with HFD feeding. the of ovarian hormones had a large protective effect against weight of ovarian hormones effect to serum with HFD the and had of serum TG and did not serum TG OVX, for mice. This is with the increased rate associated with loss of ovarian hormones in F. E. B.S. S. B. menopause not in lipoprotein metabolism Clin. 2010; 95: PubMed Scopus Google Scholar). an absence of weight gain, CETP mice OVX mice not serum TG levels in response to which affect HDL because of lipid transfer by major of studies to how defined changes in metabolism associated with obesity affect HDL composition. in proteins in CETP mice compared with from human HDL S. J. S. S. P. proteomics and in the of Clin. Invest. PubMed Scopus Google Scholar). Human studies have the of HDL composition an of HDL function. studies are in and effect of metabolic changes and HDL composition because represent from a and in lipid metabolism, and In studies we have CETP mice, which are and were for composition at to mice the CETP to in CETP expression associated with and changes in ovarian hormones In we defined changes in HDL composition due to changes in changes in response to OVX, and the of that in TG metabolism related with ovarian in insulin with HFD-feeding in SHAM mice were by the protein composition of HDL, we that changes were due to HFD-feeding in OVX mice, compared with HFD-feeding in SHAM mice. to HDL composition from the we at the of HDL proteins a a large number of proteins to the HDL proteins to the SHAM proteins to to between proteins were not in HDL from SHAM mice. of of proteins HDL function to be we a of proteins related to coagulation, and lipid metabolism. This is in to the SHAM for which we proteins to to between of proteins by may the which is to associated HDL proteins compared with with (8Collins L.A. Olivier M. Quantitative comparison of lipoprotein fractions derived from human plasma and serum by liquid chromatography-tandem mass spectrometry.Proteome Sci. 2010; 8: 42Crossref PubMed Scopus (16) Google Scholar). of proteins involved in glucose metabolism in the OVX may the of impaired glucose metabolism with HDL protein changes the that OVX in CETP mice a to HDL composition. the that HFD feeding protein changes in HDL ovarian hormones are we to proteins between we a of HFD feeding OVX than in SHAM mice. that HFD feeding altered of the HDL proteins OVX proteins of proteins compared with less than of HDL proteins altered with HFD feeding SHAM of proteins were low number of mice is a to the of proteins that were between a of HFD feeding on HDL composition OVX is that the in protein levels OVX than HFD feeding for SHAM mice the we in and that were not with HFD feeding in SHAM mice. These changes the absence of insulin of serum TG in OVX mice that in insulin to in HDL composition between SHAM and OVX were during the hyperglycemic clamp less These suggest that the of ovarian hormones from changes in HDL composition in the of HFD feeding. These studies define the of HFD loss of ovarian and the of HDL composition. studies of menopause and cardiovascular risk in have and a studies did not the of acute loss of ovarian hormones cardiovascular risk at to and weight gain E. and risk for coronary heart J. 1989; PubMed Scopus Google Scholar, D.M. and of coronary in J. Clin. PubMed Scopus Google M. and risk of cardiovascular disease by and PubMed Scopus Google Scholar). the of the from to and influences obesity and HDL levels E. R.H. and in of the 2011; PubMed Scopus Google Scholar). and obesity affect VLDL in B. S. of and obesity on J. Clin. PubMed Scopus Google Scholar). define the HDL of female CETP mice and changes in HDL composition to a well defined of composition, and glucose and TG metabolism. These that there are large changes in protein composition in HDL that are not revealed by of the cholesterol content of HDL. there are changes in lipoprotein levels and composition that are not in suggest that CETP-expressing mice be a model to how HDL composition changes in response to metabolic by the the Proteomics and and the with cholesteryl ester transfer protein high-fat diet lipoprotein low-fat diet ovariectomy protein triglyceride

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