Coordinated Control of Cholesterol Catabolism to Bile Acids and of Gluconeogenesis via a Novel Mechanism of Transcription Regulation Linked to the Fasted-to-fed Cycle

Abstract

Bile acid metabolism plays an essential role in cholesterol homeostasis and is critical for the initiation of atherosclerotic disease. However, despite the recent advances, the molecular mechanisms whereby bile acids regulate gene transcription and cholesterol homeostasis in mammals still need further investigations. Here, we show that bile acids suppress transcription of the gene (CYP7A1) encoding cholesterol 7α-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis, also through an unusual mechanism not involving the bile acid nuclear receptor, farnesoid X receptor. By performing cell-based reporter assays, protein/protein interaction, and chromatin immunoprecipitation assays, we demonstrate that bile acids impair the recruitment of peroxisome proliferator-activated receptor-γ coactivator-1α and cAMP response element-binding protein-binding protein by hepatocyte nuclear factor-4α, a master regulator of CYP7A1. We also show for the first time that bile acids inhibit transcription of the gene (PEPCK) encoding phosphoenolpyruvate carboxykinase, the rate-limiting enzyme in gluconeogenesis, through the same farnesoid X receptor-independent mechanism. Chromatin immunoprecipitation assay revealed that bile acid-induced dissociation of coactivators from hepatocyte nuclear factor-4α decreased the recruitment of RNA polymerase II to the core promoter and downstream in the 3′-untranslated regions of these two genes, reflecting the reduction of gene transcription. Finally, we found that Cyp7a1 expression was stimulated in fasted mice in parallel to Pepck, whereas the same genes were repressed by bile acids. Collectively, these results reveal a novel regulatory mechanism that controls gene transcription in response to extracellular stimuli and argue that the transcription regulation by bile acids of genes central to cholesterol and glucose metabolism should be viewed dynamically in the context of the fasted-to-fed cycle. Bile acid metabolism plays an essential role in cholesterol homeostasis and is critical for the initiation of atherosclerotic disease. However, despite the recent advances, the molecular mechanisms whereby bile acids regulate gene transcription and cholesterol homeostasis in mammals still need further investigations. Here, we show that bile acids suppress transcription of the gene (CYP7A1) encoding cholesterol 7α-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis, also through an unusual mechanism not involving the bile acid nuclear receptor, farnesoid X receptor. By performing cell-based reporter assays, protein/protein interaction, and chromatin immunoprecipitation assays, we demonstrate that bile acids impair the recruitment of peroxisome proliferator-activated receptor-γ coactivator-1α and cAMP response element-binding protein-binding protein by hepatocyte nuclear factor-4α, a master regulator of CYP7A1. We also show for the first time that bile acids inhibit transcription of the gene (PEPCK) encoding phosphoenolpyruvate carboxykinase, the rate-limiting enzyme in gluconeogenesis, through the same farnesoid X receptor-independent mechanism. Chromatin immunoprecipitation assay revealed that bile acid-induced dissociation of coactivators from hepatocyte nuclear factor-4α decreased the recruitment of RNA polymerase II to the core promoter and downstream in the 3′-untranslated regions of these two genes, reflecting the reduction of gene transcription. Finally, we found that Cyp7a1 expression was stimulated in fasted mice in parallel to Pepck, whereas the same genes were repressed by bile acids. Collectively, these results reveal a novel regulatory mechanism that controls gene transcription in response to extracellular stimuli and argue that the transcription regulation by bile acids of genes central to cholesterol and glucose metabolism should be viewed dynamically in the context of the fasted-to-fed cycle. A fundamental problem in biology is understanding the mechanisms by which extracellular stimuli transduce their signal to the nucleus and affect gene transcription. Genes are expressed in temporal and spatial pattern during development and can be regulated by hormonal and dietary stimuli or by pathogenic factors, thus contributing to disease initiation and progression. The appreciation of such mechanisms can help to unravel disease pathogenesis or even disclose targets for novel therapeutic interventions. A typical example is the mechanism whereby bile acids regulate their own synthesis by acting on transcription of the gene (CYP7A1) encoding cholesterol 7α-hydroxylase, the rate-limiting enzyme of the so-called “classic” pathway (1Javitt N.B. FASEB J. 1994; 8: 1308-1311Crossref PubMed Scopus (143) Google Scholar, 2Chiang J.Y.L. Endocr. Rev. 2002; 23: 443-463Crossref PubMed Scopus (375) Google Scholar). CYP7A1 has been implicated in genetic susceptibility to atherosclerosis (3Spady D.K. Cuthbert J.A. Willard M.N. Meidell R.S. J. Biol. Chem. 1998; 273: 126-132Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 4Pullinger C.R. Eng C. Salen G. Shefer S. Batta A.K. Erickson S.K. Verhagen A. Rivera C.R. Mulvihill S.J. Malloy M.J. Kane J.P. J. Clin. Invest. 2002; 110: 109-117Crossref PubMed Scopus (433) Google Scholar) because it controls the main route whereby cholesterol is removed from the body in mammals (2Chiang J.Y.L. Endocr. Rev. 2002; 23: 443-463Crossref PubMed Scopus (375) Google Scholar, 5Russell D.W. Setchell K.D.R. Biochemistry. 1992; 31: 4737-4749Crossref PubMed Scopus (646) Google Scholar). The most relevant type of regulation of CYP7A1 is the feedback that bile acids exert on the expression of this gene (2Chiang J.Y.L. Endocr. Rev. 2002; 23: 443-463Crossref PubMed Scopus (375) Google Scholar). The complete understanding of such mechanisms represents an opportunity to describe unusual regulatory circuits controlling gene transcription and is of great value for potential biomedical applications in the design of new generations of drugs affecting cholesterol metabolism. Stroup et al. (6Stroup D. Crestani M. Chiang J.Y. Am. J. Physiol. 1997; 273: G508-G517PubMed Google Scholar) first identified a bile acid-responsive element (BARE) 1The abbreviations used are: BARE, bile acid-responsive element; HNF-4α, hepatocyte nuclear factor-4α; FTF, α-fetoprotein transcription factor; FXR, farnesoid X receptor; Shp, small heterodimer partner; MAPK, mitogen-activated protein kinase; PGC-1α, peroxisome proliferator-activated receptor-γ coactivator-1α; CBP, cAMP response element-binding protein-binding protein; PEPCK, phosphoenolpyruvate carboxykinase; HA, hemagglutinin; CDCA, chenodeoxycholic acid; UDCA, ursodeoxycholic acid; HRU, hormone response unit; LBD, ligand-binding domain.1The abbreviations used are: BARE, bile acid-responsive element; HNF-4α, hepatocyte nuclear factor-4α; FTF, α-fetoprotein transcription factor; FXR, farnesoid X receptor; Shp, small heterodimer partner; MAPK, mitogen-activated protein kinase; PGC-1α, peroxisome proliferator-activated receptor-γ coactivator-1α; CBP, cAMP response element-binding protein-binding protein; PEPCK, phosphoenolpyruvate carboxykinase; HA, hemagglutinin; CDCA, chenodeoxycholic acid; UDCA, ursodeoxycholic acid; HRU, hormone response unit; LBD, ligand-binding domain. located at nucleotides -149 to -128 of CYP7A1, which contains hormone response element-like sequences recognized by several members of the nuclear receptor superfamily, such as hepatocyte nuclear factor-4α (HNF-4α; NR2A1), chicken ovalbumin upstream promoter-transcription factor II (NR2F2), and α-fetoprotein transcription factor (FTF), also known as the CYP7A1 promoter-binding factor or liver receptor homolog-1 (NR5A2) (7Crestani M. 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However, recent from that FXR, the small heterodimer and are not the nuclear that are this for we that bile acids inhibit the transcription of CYP7A1 by the potential of HNF-4α, a of CYP7A1, a mitogen-activated protein A. Galli G. Crestani M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). by et al. D. S. C. S. M. Moore D. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar) and Kerr et al. S. M. K. S. Shan B. D. M. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar) that bile acids can CYP7A1 transcription in an thus the in in results the of the molecular the regulatory mechanisms of CYP7A1 transcription by bile acids through the nuclear receptor A in the bile acid-induced dissociation of the and transcription coactivators to the on the core promoter of genes J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the coactivators by bile acid we peroxisome proliferator-activated receptor-γ coactivator-1α and cAMP response element-binding protein-binding protein and and The of is also a in the regulation of the gene encoding the enzyme phosphoenolpyruvate (PEPCK) in response to the S. S. A. D. G. C. B. M. PubMed Scopus Google Scholar, G. J. J. G. J. C.R. D.K. PubMed Scopus Google Scholar). is a of bile acid in liver A. Galli G. Crestani M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google we the that bile acids affect the of these transcription we show for the first time that bile acids suppress the transcription of CYP7A1 by the of the coactivators and we found that PEPCK, a of the that the response to G. J. J. G. J. C.R. D.K. PubMed Scopus Google is to the same regulation by bile acids in and in We also that Cyp7a1 is stimulated in parallel in fasted bile acids as of glucose and metabolism. expression and the reporter two of the response element in of the promoter were by The the CYP7A1 was Stroup D. M. Crestani M. Galli G. Chiang J.Y.L. J. Lipid Res. Full Text PDF PubMed Google Scholar). The and the expression for CBP, receptor transcription the and the of the receptor, and were from of and The the of to the has been A. Galli G. Crestani M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The and in the and sequences were from K. of The expression for in was by of The was by and the and were in were by the as A. Galli G. Crestani M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of reporter of receptor of expression or an of and of in were for in in the of chenodeoxycholic acid or by or an of or were also for a for the of on gene we also in which were ursodeoxycholic acid and were as A. Galli G. Crestani M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and are expressed as of was at were the of and for in were and RNA was the RNA to the of RNA from was II the and of the to of the were to a the to CYP7A1, PEPCK, HNF-4α, and was used as the gene for and was in the same for were and to in a of of a at for and an at for The used for were by are The of the was by performing at the of of the a thus reflecting the of the were at and were or and or were or in for were in assay and of were protein and for by an protein The were the same and and were by were or were by by to the of an to the the expression and the receptor protein/protein or and in HNF-4α, from the coactivators and or were of for as by and by Chromatin the were or for in and chromatin was for at was and were and on for in were in and were a on to from to for the to in a chromatin were chromatin immunoprecipitation and protein and the for at were on protein and and and and and were and at for and the of to was at for A and for at were and from and were by as a for the of on recruitment of coactivators to the CYP7A1 and genes, we also The used were and polymerase II were to the CYP7A1 nucleotides to to the CYP7A1 upstream nucleotides to to the CYP7A1 nucleotides to to the CYP7A1 3′-untranslated nucleotides to of the hormone response nucleotides to to the upstream nucleotides to to the nucleotides to to the and 3′-untranslated nucleotides to of the are mice to were on a to on a or a acid for to and the of on gene mice the were for and mice the same to were and and RNA was an and to the was by as were the at Bile Acids and CYP7A1 an that bile acids the transcription of CYP7A1 by affecting the potential of the nuclear receptor an pathway A. Galli G. Crestani M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We to the of bile acids on is to the initiation of the this we used a assay in the of the transcription factor and that repressed the of this nuclear receptor the P.R. D.J. G. K.D. Moore L.B. Wilson J.G. Lewis M.C. Jones S.A. Willson T.M. J. Chem. 2000; PubMed Scopus Google Scholar) not affect the potential of The of this was in a assay the which was not by or that and transcription and repressed the transcription of CYP7A1 parallel assays, the bile acid not affect the transcription of CYP7A1 or the of not results that bile acids CYP7A1 transcription and the involving the nuclear receptor Bile Acids CYP7A1 by the bile acids affect the transcription of CYP7A1, we the role of transcription We that bile acids affect the transcription of CYP7A1 by the of the a in this we PGC-1α, a that is implicated in the transcription regulation of genes a role in and metabolism G. J. J. G. J. C.R. D.K. PubMed Scopus Google Scholar, M. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, D. A. Full Text Full Text PDF PubMed Scopus Google Scholar). We bile acids affect the recruitment of by to the CYP7A1 promoter a in this we protein/protein by were an expression for and or were were by and an to the of on the and the of that not the protein of and and from G. J. J. G. J. C.R. D.K. PubMed Scopus Google immunoprecipitation was the of HNF-4α, was whereas the of HNF-4α, and this further bile acids exert their at the of or we the by in to this we in the from that bile acids a or of the nuclear receptor that for We in the of the of the by bile acids. were the CYP7A1 gene Stroup D. M. Crestani M. Galli G. Chiang J.Y.L. J. Lipid Res. Full Text PDF PubMed Google Scholar) and CDCA, of or a of the two repressed the of the CYP7A1 promoter cAMP stimulated the transcription of by the CYP7A1 promoter However, were in the of to the promoter of the CYP7A1 The gene not to of the that by the expression of cAMP the transcription of CYP7A1 and the bile of CYP7A1 promoter by the of the this we the transcription of the CYP7A1 gene the expression for in the or of bile acids. the CYP7A1 transcription of the reporter gene However, the expression of the of on CYP7A1 transcription and stimulated the promoter of CYP7A1, the of the CYP7A1 promoter in the of these on HNF-4α, we assays, the expression repressed the transcription of the protein The of transcription most the of bile acids However, to the transcription of the which the for the coactivators by the ligand-binding G. J. J. G. J. C.R. D.K. 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Chem. 1999; Full Text Full Text PDF PubMed Scopus Google and we the of bile acids on the in in the expression decreased the of that the of the expression of and We the of the and of by and that most we found that the of of the receptor PGC-1α, of in from and in the in that the of the feedback regulation of the CYP7A1 gene by CDCA, not affect the of the CYP7A1 promoter the the expression of the of on of the as from also to be in the regulation of CYP7A1 transcription by bile acids. stimulated the transcription of and the acids not that of the acids Bile Acids and cAMP the of the of we the of CYP7A1, PGC-1α, and in CDCA, or a of the two by the of CYP7A1 at the same the expression of as T.T. Makishima M. Repa J.J. Schoonjans K. Kerr T.A. Auwerx J. Mangelsdorf D.J. Mol. Cell. 2000; 6: 507-515Abstract Full Text Full Text PDF PubMed Scopus (1196) Google Scholar, 10Goodwin B. Jones S.A. Price R.R. Watson M.A. McKee D.D. Moore L.B. Galardi C. Wilson J.G. Lewis M.C. Roth M.E. Maloney P.R. Willson T.M. Kliewer S.A. Mol. Cell. 2000; 6: 517-526Abstract Full Text Full Text PDF PubMed Scopus (1453) Google not the of and cAMP to the cAMP response element in the promoter of this S. S. A. D. G. C. B. M. PubMed Scopus Google Scholar). the in cAMP also the of CYP7A1, that the cholesterol gene is a of the in liver was in it to the transcription of CYP7A1, the of in the feedback regulation of CYP7A1 by bile acids the decreased the of CYP7A1 at the same that of not the of and Bile Acids the of in the that bile acids the protein/protein and the coactivators and to this type of regulation also to The liver gene PEPCK, which the enzyme the rate-limiting of gluconeogenesis, is the of the which is to a S. S. A. D. G. C. B. M. PubMed Scopus Google Scholar, G. J. J. G. J. C.R. D.K. PubMed Scopus Google Scholar). 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Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). is that bile acids the of these and the of the receptor as as for be to or can affect the recruitment of coactivators in the of and bile acids can these was to that the of not the transcription of these two genes, as to the of to the of as a for the of and of through the G. M. J. B. Science. 1999; PubMed Scopus Google Scholar). The of in be to in the of the the the of the of not the of H. M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google it be by in the However, in the context of the and CYP7A1 the of the of not to be in to the expression of these two genes, the of The the as to which of the two bile is relevant for the regulation of CYP7A1 and gene transcription. The that the pathway be critical for these two bile acids can still the of Cyp7a1 in not liver receptor and by bile acids on to the and sequences in the the promoter be as a of the CYP7A1 that to bile acids also the not the transcription of because FTF, the of not this is in a recent that is a novel for J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). However, it should be that the of was in stimulated by whereas we the of bile acids and the on transcription because synthesis of through FXR, it is that the by in time because it is by involving an pathway A. Galli G. Crestani M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). is by the that to regulation of own a as an essential for the bile acid-induced dissociation of the that can affect the of in Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, S. A. PubMed Scopus Google Scholar, B. A. M. Mol. Cell. Biol. 1997; PubMed Scopus Google Scholar, H. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The pathway a role in and the through we a novel mechanism of transcription regulation affecting genes in bile acid synthesis and that mice are still to bile acids. The discovery that bile acids also the transcription of PEPCK, the rate-limiting enzyme of gluconeogenesis, new on the of new mechanisms for the design of novel of such as and We K. and for the of the and of the used in this We are also to and for on and for We also of for the and for help