Enlargement of High Density Lipoprotein in Mice via Liver X Receptor Activation Requires Apolipoprotein E and Is Abolished by Cholesteryl Ester Transfer Protein Expression

Abstract

The factors involved in the generation of larger high density lipoprotein (HDL) particles, HDL1 and HDLc, are still not well understood. Administration of a specific synthetic liver X receptor (LXR) agonist, T0901317, in mice resulted in an increase of not only HDL cholesterol but also HDL particle size (Cao, G., Beyer, T. P., Yang, X. P., Schmidt, R. J., Zhang, Y., Bensch, W. R., Kauffman, R. F., Gao, H., Ryan, T. P., Liang, Y., Eacho, P. I., and Jiang, X. C. (2002) J. Biol. Chem. 277, 39561–39565). We have investigated the roles that apoE and CETP may play in this process. We treated apoE-deficient, cholesterol ester transport protein (CETP) transgenic, and wild type mice with various doses of the LXR agonist and monitored their HDL levels. Fast protein liquid chromatography and apolipoprotein analysis revealed that in apoE knockout mouse plasma, there was neither induction of larger HDL formation nor increase of HDL cholesterol, suggesting that apoE is essential for the LXR agonist effects on HDL metabolism. In CETP transgenic mice, CETP expression completely abolished LXR agonist-mediated HDL enlargement and greatly attenuated HDL cholesterol levels. Analysis of HDL particles by electron microscope and nondenaturing gel electrophoresis revealed similar findings. In apoE-deficient mice, LXR agonist also produced a significant increase in very low density lipoprotein/low density lipoprotein cholesterol and apolipoprotein B content. Our studies provide direct evidence that apoE and CETP are intimately involved in the accumulation of the enlarged HDL (HDL1 or HDLc) particles in mice. The factors involved in the generation of larger high density lipoprotein (HDL) particles, HDL1 and HDLc, are still not well understood. Administration of a specific synthetic liver X receptor (LXR) agonist, T0901317, in mice resulted in an increase of not only HDL cholesterol but also HDL particle size (Cao, G., Beyer, T. P., Yang, X. P., Schmidt, R. J., Zhang, Y., Bensch, W. R., Kauffman, R. F., Gao, H., Ryan, T. P., Liang, Y., Eacho, P. I., and Jiang, X. C. (2002) J. Biol. Chem. 277, 39561–39565). We have investigated the roles that apoE and CETP may play in this process. We treated apoE-deficient, cholesterol ester transport protein (CETP) transgenic, and wild type mice with various doses of the LXR agonist and monitored their HDL levels. Fast protein liquid chromatography and apolipoprotein analysis revealed that in apoE knockout mouse plasma, there was neither induction of larger HDL formation nor increase of HDL cholesterol, suggesting that apoE is essential for the LXR agonist effects on HDL metabolism. In CETP transgenic mice, CETP expression completely abolished LXR agonist-mediated HDL enlargement and greatly attenuated HDL cholesterol levels. Analysis of HDL particles by electron microscope and nondenaturing gel electrophoresis revealed similar findings. In apoE-deficient mice, LXR agonist also produced a significant increase in very low density lipoprotein/low density lipoprotein cholesterol and apolipoprotein B content. Our studies provide direct evidence that apoE and CETP are intimately involved in the accumulation of the enlarged HDL (HDL1 or HDLc) particles in mice. Epidemiological studies have firmly established that plasma HDL 1The abbreviations used are: HDLhigh density lipoproteinABCA1ATP binding cassette transporter A1CETPcholesterol ester transport proteinCETP-TgCETP transgenicapoEapolipoprotein EapoAIapolipoprotein AILXRliver X receptorPLTPphospholipid transfer proteinLDLlow density lipoproteinLDLRlow density lipoprotein receptorFPLCfast protein liquid chromatography.1The abbreviations used are: HDLhigh density lipoproteinABCA1ATP binding cassette transporter A1CETPcholesterol ester transport proteinCETP-TgCETP transgenicapoEapolipoprotein EapoAIapolipoprotein AILXRliver X receptorPLTPphospholipid transfer proteinLDLlow density lipoproteinLDLRlow density lipoprotein receptorFPLCfast protein liquid chromatography. cholesterol is inversely correlated to coronary artery events (1.Wierzbicki A.S. Mikhailidis D.P. Curr. Med. Res. Opin. 2002; 18: 36-44Crossref PubMed Scopus (37) Google Scholar). The biogenesis of HDL is thought to originate from the secretion of its major apolipoprotein component, apoAI, from the liver and the small intestine. ApoAI enters the circulation and interacts with and removes excessive free cholesterol from peripheral tissues, forming disc-like nascent HDL particles. ApoAI-dependent phospholipid and cholesterol efflux from peripheral tissues requires the protein ABCA1, an ATP binding cassette transporter (2.Attie A.D. Kastelein J.P. Hayden M.R. J. Lipid Res. 2001; 42: 1717-1726Abstract Full Text Full Text PDF PubMed Google Scholar). The maturation of HDL depends on both lecithin-cholesterol acyltransferase and phospholipid transfer protein (PLTP) activities. The former esterifies free cholesterol to form spherical HDL (3.Eisenberg S. J. Lipid Res. 1984; 25: 1017-1058Abstract Full Text PDF PubMed Google Scholar), and the latter transfers phospholipid from triglyceride-rich lipoproteins into the nascent HDL particles (4.Jiang X.C. Bruce C. Mar J. Lin M. Ji Y. Francone O.L. Tall A.R. J. Clin. Invest. 1999; 103: 907-914Crossref PubMed Scopus (319) Google Scholar). Cholesteryl ester transfer protein (CETP) catalyzes transfer of cholesteryl ester from mature HDL into apoB-containing lipoproteins for catabolism through liver low density lipoprotein receptor (LDLR) (5.Tall A.R. Jiang X. Luo Y. Silver D. Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1185-1188Crossref PubMed Scopus (116) Google Scholar). HDL cholesterol can also be delivered to the liver via scavenger receptor BI, the HDL receptor, through the process of selective cholesterol uptake (6.Acton S. Rigotti A. Landschulz K.T. Xu S. Hobbs H.H. Krieger M. Science. 1996; 271: 518-520Crossref PubMed Scopus (1974) Google Scholar). It is conceivable that the regulation of ABCA1, lecithin-cholesterol acyltransferase, PLTP, CETP, and scavenger receptor BI would have an important impact on HDL metabolism, including particle catabolic rate, lipid composition, and particle size. high density lipoprotein ATP binding cassette transporter A1 cholesterol ester transport protein CETP transgenic apolipoprotein E apolipoprotein AI liver X receptor phospholipid transfer protein low density lipoprotein low density lipoprotein receptor fast protein liquid chromatography. high density lipoprotein ATP binding cassette transporter A1 cholesterol ester transport protein CETP transgenic apolipoprotein E apolipoprotein AI liver X receptor phospholipid transfer protein low density lipoprotein low density lipoprotein receptor fast protein liquid chromatography. Liver X receptors were initially isolated as orphan nuclear receptors. Two isoforms, LXRα and LXRβ, exist with different expression patterns (7.Lu T.T. Repa J.J. Mangelsdorf D.J. J. Biol. Chem. 2001; 276: 37735-37738Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar). Oxysterols were identified as their native ligands, implicating their role in cholesterol metabolism (8.Janowski B.A. Willy P.J. Devi T.R. Falck J.R. Mangelsdorf D.J. Nature. 1996; 383: 728-731Crossref PubMed Scopus (1428) Google Scholar). Disruption of LXRα in mice led to dramatic accumulation of hepatic cholesterol when the mice were fed a high cholesterol diet (9.Peet D.J. Turley S.D. Ma W. Janowski B.A. Lobaccaro J.M. Hammer R.E. Mangelsdorf D.J. Cell. 1998; 93: 693-704Abstract Full Text Full Text PDF PubMed Scopus (1225) Google Scholar). The resulting phenotype was largely from a failure to up-regulate cholesterol 7α-hydroxylase (Cyp7a), the rate-limiting step in the conversion of cholesterol to bile acids. Since then, multiple LXR target genes, including ABCA1 (10.Costet P. Luo Y. Wang N. Tall A.R. J. Biol. Chem. 2000; 275: 28240-28245Abstract Full Text Full Text PDF PubMed Scopus (840) Google Scholar), apoE (11.Laffitte B.A. Repa J.J. Joseph S.B. Wilpitz D.C. Kast H.R. Mangelsdorf D.J. Tontonoz P. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 507-512Crossref PubMed Scopus (561) Google Scholar), CETP (12.Luo Y. Tall A.R. J. Clin. Invest. 2000; 105: 513-520Crossref PubMed Scopus (304) Google Scholar), and PLTP (13.Cao G. Beyer T.P. Yang X.P. Schmidt R.J. Zhang Y. Bensch W.R. Kauffman R.F. Gao H. Ryan T.P. Liang Y. Eacho P.I. Jiang X.C. J. Biol. Chem. 2002; 277: 39561-39565Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 14.Mak P.A. Kast-Woelbern H.R. Anisfeld A.M. Edwards P.A. J. Lipid Res. 2002; 43: 2037-2041Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar), have been identified, indicating the critical role of LXR in regulating HDL metabolism. It has also been reported recently that LXRs also play a central role in regulating fatty acid biosynthesis (15.Schultz J.R. Tu H. Luk A. Repa J.J. Medina J.C. Li L. Schwendner S. Wang S. Thoolen M. Mangelsdorf D.J. Lustig K.D. Shan B. Genes Dev. 2000; 14: 2831-2838Crossref PubMed Scopus (1373) Google Scholar, 16.Repa J.J. Liang G. Ou J. Bashmakov Y. Lobaccaro J.M. Shimomura I. Shan B. Brown M.S. Goldstein J.L. Mangelsdorf D.J. Genes Dev. 2000; 14: 2819-2830Crossref PubMed Scopus (1393) Google Scholar), glucose metabolism (17.Cao G. Liang Y. Broderick C.L. Oldham B.A. Beyer T.P. Schmidt R.J. Zhang Y. Stayrook K.R. Suen C. Otto K.A. Miller A.R. Dai J. Foxworthy P. Gao H. Ryan T.P. Jiang X.C. Burris T.P. Eacho P.I. Etgen G.J. J. Biol. Chem. 2003; 278: 1131-1136Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar), and inflammation process (18.Fowler A.J. Sheu M.Y. Schmuth M. Kao J. Fluhr J.W. Rhein L. Collins J.L. Willson T.M. Mangelsdorf D.J. Elias P.M. Feingold K.R. J. 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Invest. 1999; 103: 907-914Crossref PubMed Scopus (319) Google Scholar). electron was a electron microscope in and were with an of on a the liquid was the was to and the was were from with ABCA1 and PLTP were by an was used to a of from mouse for ABCA1 The resulting was into and The resulting was and was the was the was used for analysis by a from The for PLTP was (13.Cao G. Beyer T.P. Yang X.P. Schmidt R.J. Zhang Y. Bensch W.R. Kauffman R.F. Gao H. Ryan T.P. Liang Y. Eacho P.I. Jiang X.C. J. Biol. Chem. 2002; 277: 39561-39565Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar). The was with an was that of mice with a specific LXR agonist, T0901317, resulted in an increase of both HDL cholesterol and particle size (13.Cao G. Beyer T.P. Yang X.P. Schmidt R.J. Zhang Y. Bensch W.R. Kauffman R.F. Gao H. Ryan T.P. Liang Y. Eacho P.I. Jiang X.C. J. Biol. Chem. 2002; 277: 39561-39565Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar). the of apoE on the formation of enlarged HDL particles, as well as on HDL cholesterol treated mice with and for type mice were treated in a similar for reported (13.Cao G. Beyer T.P. Yang X.P. Schmidt R.J. Zhang Y. Bensch W.R. Kauffman R.F. Gao H. Ryan T.P. Liang Y. Eacho P.I. Jiang X.C. J. Biol. Chem. 2002; 277: 39561-39565Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar), of mice with resulted in dramatic increase in HDL cholesterol, as by The HDL a as well as a was largely in mice. latter with that of the on its size and the of and The apoE of was by of plasma apoE was as by the the was not (13.Cao G. Beyer T.P. Yang X.P. Schmidt R.J. Zhang Y. Bensch W.R. Kauffman R.F. Gao H. Ryan T.P. Liang Y. Eacho P.I. Jiang X.C. J. Biol. Chem. 2002; 277: 39561-39565Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar). The of both HDL was by analysis of by The from size were and and were to was to and with to apolipoprotein AI or E or apolipoprotein S. were with and were from wild type and CETP transgenic mice In mice, major lipoprotein and HDL a of the was increase in HDL size or HDL cholesterol the LXR agonist the the that HDL cholesterol increase was and of cholesterol LXR agonist was with a of lipoprotein particles. In and of the mice, there was a increase in the cholesterol and an increase of was in as was in mice A.S. J.L. PubMed Scopus Google and was by with ApoAI was not in and to be in in to LXR agonist of the LXR agonist to mice not to HDL particle enlargement or an increase in HDL cholesterol levels. cholesterol in particles was the role of CETP in the LXR agonist-mediated in HDL cholesterol metabolism, a transgenic in the CETP was the of the U. R.E. J. Lipid Res. Full Text PDF PubMed Google Scholar). LXRs are not to (15.Schultz J.R. Tu H. Luk A. Repa J.J. Medina J.C. Li L. Schwendner S. Wang S. Thoolen M. Mangelsdorf D.J. Lustig K.D. Shan B. Genes Dev. 2000; 14: 2831-2838Crossref PubMed Scopus (1373) Google Scholar), and that of mice with not in a in plasma CETP not of mice with not to the formation of enlarged HDL particles as was in mice. small increase in HDL cholesterol was only the of the significant increase of or apoE in the HDL was CETP expression greatly attenuated the LXR HDL cholesterol increase and abolished the increase in HDL particle size. the HDL cholesterol and particle size in different of the LXR agonist, nondenaturing gel electrophoresis to HDL particles. plasma were to the nondenaturing were with HDL particles were and on the particles not into the gel of the size. In mice, the of of HDL in a an increase in HDL lipid HDL particle size enlargement was also In mice, there was HDL lipid but in particle size LXR agonist In CETP transgenic mice, LXR agonist not HDL particle and the increase of HDL lipid was attenuated the analysis of HDL cholesterol and particle size with nondenaturing the of In to the HDL particles from particles by The isolated HDL were to electron The HDL particle size from wild type was in the of in resulted in an enlargement of HDL particles. The size of HDL particle in the in apoE-deficient mice or CETP transgenic mice not significant in HDL particle size The isolated HDL were by native gel electrophoresis and with electron of wild type mice resulted in of HDL particles in the native gel nondenaturing suggesting the increase in HDL particle size. of apoE-deficient mice or CETP transgenic mice, not in in the of HDL particles. The of and apoE in HDL particles isolated from was with analysis in both and apoE in HDL particles of wild type mice was was in apoE-deficient mice or CETP transgenic mice. We apolipoprotein analysis on isolated and HDL from wild type mouse plasma with or LXR agonist can be from the isolated significant of and The isolated HDL particles the LXR agonist greatly apoE and levels. Since HDL particles from LXR plasma HDL and enlarged the that the not of analysis of from isolated mouse plasma with or LXR agonist HDL and were by as was on and the were by as the of the regulation of important LXR target genes, ABCA1 and PLTP, in the of mice resulted in a induction of ABCA1 and a increase of In mice, both ABCA1 and PLTP was and In CETP transgenic mice, ABCA1 and PLTP were also by LXR agonist and and the regulation of ABCA1 and PLTP not to be different in the suggesting the direct roles of apoE and CETP expression in the LXR agonist-mediated HDL cholesterol metabolism. LXR are to HDL cholesterol in mice. In this for the that LXR agonist-mediated increase in HDL particle size and cholesterol requires LXR agonist-mediated HDL enlargement is completely abolished by CETP and LXRs up-regulate ABCA1 in the LXR enlarged HDL particles are (13.Cao G. Beyer T.P. Yang X.P. Schmidt R.J. Zhang Y. Bensch W.R. Kauffman R.F. Gao H. Ryan T.P. Liang Y. Eacho P.I. Jiang X.C. J. Biol. Chem. 2002; 277: 39561-39565Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar). is similar to an HDL HDL1 or C. J. Biol. Chem. Full Text PDF PubMed Google Scholar). HDL1 particles have been for the of particles in is still understood. J. Biol. Chem. Full Text PDF PubMed Google used HDL and or particles to that small HDL particles be into HDL1 particles in the of excessive cholesterol in a lecithin-cholesterol It was also reported in HDL1 formation depends on the of can be from from plasma or C. J. Biol. Chem. Full Text PDF PubMed Google Scholar). In that the enlargement of HDL LXR agonist was in mice and indicating similar to the in C. J. Biol. Chem. Full Text PDF PubMed Google Scholar), apoE is for the formation of The by HDL with apoE in LXR mice is not apoE with enlarged HDL particles can be from liver in the that is to HDL this may an liver apoE was not by LXR agonist (15.Schultz J.R. Tu H. Luk A. Repa J.J. Medina J.C. Li L. Schwendner S. Wang S. Thoolen M. Mangelsdorf D.J. Lustig K.D. Shan B. Genes Dev. 2000; 14: 2831-2838Crossref PubMed Scopus (1373) Google Scholar). be from peripheral tissues, and apoE expression is by LXRs in both and (11.Laffitte B.A. Repa J.J. Joseph S.B. Wilpitz D.C. Kast H.R. Mangelsdorf D.J. Tontonoz P. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 507-512Crossref PubMed Scopus (561) Google Scholar). CETP is that can the HDL1 formation A.R. J. Lipid Res. Full Text PDF PubMed Google Scholar). with CETP have HDL particles that are in apoE S. N. Y. S. J. Clin. Invest. PubMed Scopus Google Scholar, Med. Clin. N. PubMed Scopus Google Scholar). of in a increase of can to low plasma and may transport as as of the plasma cholesterol Med. Clin. N. PubMed Scopus Google Scholar). The enlarged HDL particles with apoE in mice LXR agonist are similar to the HDL1 or particles from with CETP CETP catalyzes the of cholesterol and HDL and triglyceride-rich lipoprotein particles. CETP transgenic mice plasma HDL cholesterol on the transgenic A. T. P. Jiang X.C. J.L. Tall A.R. J. Biol. Chem. Full Text PDF PubMed Google Scholar, T. T. A. P. Tall A.R. J.L. J. Clin. Invest. PubMed Scopus Google Scholar). In CETP expression in mice resulted in of enlarged HDL and and enlarged HDL particles to be and for CETP and The of the LXR agonist to HDL cholesterol was also attenuated in the CETP transgenic mice. studies in CETP, LXR agonist may not in a significant in HDL cholesterol levels. of with not to significant in HDL cholesterol, P. Beyer, P. I. Eacho, and G. is with this The of CETP to an LXR increase of HDL in may be that LXRs up-regulate CETP expression (12.Luo Y. Tall A.R. J. Clin. Invest. 2000; 105: 513-520Crossref PubMed Scopus (304) Google Scholar). the failure of the LXR agonist to increase HDL in the of CETP, would to increase the process of of cholesterol The effects of HDL1 particles on are HDL1 particles to the receptor with high S. N. Y. S. J. Clin. Invest. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar), and can for as the major of plasma lipoproteins to peripheral tissues and the liver Med. Clin. N. PubMed Scopus Google Scholar). Since particles are still of apoE and (13.Cao G. Beyer T.P. Yang X.P. Schmidt R.J. Zhang Y. Bensch W.R. Kauffman R.F. Gao H. Ryan T.P. Liang Y. Eacho P.I. Jiang X.C. J. Biol. Chem. 2002; 277: 39561-39565Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar), may have D. S. J.C. J.L. N. J. Med. PubMed Google and I. Arterioscler. Thromb. Vasc. Biol. 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Lipid Res. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). of ABCA1 in the liver through resulted in not only HDL cholesterol increase but also an increase in HDL particle size L. C.L. A. J. T. J. N. S. J. Lipid Res. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). We have that the increase of HDL cholesterol LXR agonist was by a significant increase in liver ABCA1 implicating that of HDL cholesterol increase may be from liver ABCA1 have that apoE and CETP play critical roles in the effects of LXR on HDL cholesterol metabolism. Our studies provide evidence that HDL metabolism is a process in multiple protein in a of and We for We are to Kauffman for and for the We are to and for the for the We also and for