Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine
Bile acid concentrations are controlled by a feedback regulatory pathway whereby activation of the farnesoid X receptor (FXR) represses transcription of both the CYP7A1 gene, encoding the rate-limiting enzyme in the classic bile acid synthesis pathway, and the CYP8B1 gene, required for synthesis of cholic acid. The tissue-specific roles of FXR were examined using liver- and intestine-specific FXR-null models. FXR deficiency in either liver (FxrΔL) or intestine (FxrΔIE) increased bile acid pool size. Treatment with the FXR-selective agonist GW4064 significantly repressed CYP7A1 in FxrΔL mice but not FxrΔIE mice, demonstrating that activation of FXR in intestine but not liver is required for short-term repression of CYP7A1 in liver. This intestinal-specific effect of FXR is likely mediated through induction of the hormone FGF15, which suppresses CYP7A1. In comparison to CYP7A1, FXR-mediated repression of CYP8B1 was more dependent on the presence of FXR in liver and less dependent on its presence in intestine. Consistent with these findings, recombinant FGF15 repressed CYP7A1 mRNA levels without affecting CYP8B1 expression. These data provide evidence that FXR-mediated repression of bile acid synthesis requires the complementary actions of FXR in both liver and intestine and reveal mechanistic differences in feedback repression of CYP7A1 and CYP8B1. Bile acid concentrations are controlled by a feedback regulatory pathway whereby activation of the farnesoid X receptor (FXR) represses transcription of both the CYP7A1 gene, encoding the rate-limiting enzyme in the classic bile acid synthesis pathway, and the CYP8B1 gene, required for synthesis of cholic acid. The tissue-specific roles of FXR were examined using liver- and intestine-specific FXR-null models. FXR deficiency in either liver (FxrΔL) or intestine (FxrΔIE) increased bile acid pool size. Treatment with the FXR-selective agonist GW4064 significantly repressed CYP7A1 in FxrΔL mice but not FxrΔIE mice, demonstrating that activation of FXR in intestine but not liver is required for short-term repression of CYP7A1 in liver. This intestinal-specific effect of FXR is likely mediated through induction of the hormone FGF15, which suppresses CYP7A1. In comparison to CYP7A1, FXR-mediated repression of CYP8B1 was more dependent on the presence of FXR in liver and less dependent on its presence in intestine. Consistent with these findings, recombinant FGF15 repressed CYP7A1 mRNA levels without affecting CYP8B1 expression. These data provide evidence that FXR-mediated repression of bile acid synthesis requires the complementary actions of FXR in both liver and intestine and reveal mechanistic differences in feedback repression of CYP7A1 and CYP8B1. Bile acids are amphiphilic end products of cholesterol catabolism that facilitate lipid absorption in the intestine. Bile acids are synthesized in the liver, released into the proximal intestine, and reabsorbed in the distal intestine (1Hofmann A.F. The continuing importance of bile acids in liver and intestinal disease.Arch. Intern. Med. 1999; 159: 2647-2658Crossref PubMed Scopus (632) Google Scholar). Release of bile from the gallbladder to the proximal intestine is induced by cholecystokinin, a hormone secreted from the duodenum in response to food intake (2Shaffer E.A. Review article: control of gall-bladder motor function.Aliment. Pharmacol. Ther. 2000; 14: 2-8Crossref PubMed Scopus (73) Google Scholar). Conversely, gallbladder filling is regulated by the hormone FGF15, which is secreted from the ileum in response to bile acids (3Choi M. Moschetta A. Bookout A.L. Peng L. Umetani M. Holmstrom S.R. Suino-Powell K. Xu H.E. Richardson J.A. 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Bile acids also modulate liver regeneration (14Huang W. Ma K. Zhang J. Qatanani M. Cuvillier J. Liu J. Dong B. Huang X. Moore D.D. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration.Science. 2006; 312: 233-236Crossref PubMed Scopus (506) Google Scholar) and energy expenditure (15Watanabe M. Houten S.M. Mataki C. Christoffolete M.A. Kim B.W. Sato H. Messaddeq N. Harney J.W. Ezaki O. Kodama T. et al.Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation.Nature. 2006; 439: 484-489Crossref PubMed Scopus (1508) Google Scholar). The farnesoid X receptor (FXR) is a major bile acid sensor that protects the liver from bile acid toxicity by regulating the transcription of genes involved in bile acid homeostasis. Recently, the physiological ramifications of FXR have been expanded to include broader roles in glucose and lipid homeostasis (16Cariou B. van Harmelen K. Duran-Sandoval D. van Dijk T.H. Grefhorst A. Abdelkarim M. 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FXR and in the and Lipid Res. 2006; 47: Full Text Full Text PDF PubMed Scopus Google Scholar, M. N. M. F.J. bile salt is by the farnesoid X acid 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, O. J. M. M. Farnesoid X receptor and bile are involved in regulation of the encoding the bile salt 2002; PubMed Scopus Google Scholar, S.R. The nuclear receptor for bile and J. 2006; PubMed Scopus Google Scholar). The Fxr-null been a for the roles of FXR in C.J. M. M. Ward J.M. G. Gonzalez F.J. of the nuclear receptor bile acid and lipid 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). mice to to cholic acid and with elevated cholesterol and triglyceride concentrations C.J. M. M. Ward J.M. G. Gonzalez F.J. of the nuclear receptor bile acid and lipid 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, G. M. Ward J.M. S.A. Gonzalez F.J. Sinal C.J. roles of farnesoid X X and receptor in bile acid Full Text Full Text PDF PubMed Scopus Google Scholar). The that FXR transcription of the encoding the hormone in intestine a for FXR in the intestine and liver. with the nuclear receptor expression is also regulated by to CYP7A1 and bile acid synthesis in liver B. Jones S.A. M.A. D.D. Moore C. Wilson et regulatory of the nuclear and represses bile acid 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, J.A. G. J. M. Wang S.A. et of a for the of bile acid PubMed Scopus Google Scholar, T. M. Moschetta A. Peng L. C.L. G. Jones S.A. B. Richardson J.A. et functions to bile acid Full Text Full Text PDF PubMed Scopus Google Scholar). of the importance of FXR in liver and intestine in regulating bile acid homeostasis not been owing to the of tissue-specific Fxr-null In provide the and comparison of liver- and intestine-specific Fxr-null that FXR in intestine is for feedback regulation of bile acid synthesis in liver. reveal differences in the whereby FXR represses CYP7A1 and CYP8B1. of Fxr-null mice C.J. M. M. Ward J.M. G. Gonzalez F.J. of the nuclear receptor bile acid and lipid 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) and mice T. M. Moschetta A. Peng L. C.L. G. Jones S.A. B. Richardson J.A. et functions to bile acid Full Text Full Text PDF PubMed Scopus Google Scholar) was and the Fxr-null mice (FxrΔL) and intestine-specific Fxr-null mice mice C.J. M. M. Ward J.M. G. Gonzalez F.J. of the nuclear receptor bile acid and lipid 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) were with mice the the control of the mice, from A. H. B. D. M. D. and development in a using the in Endocrinol. 12: PubMed Google and mice, from L. K. E. of the control expression in of the and of the 2002; Full Text Full Text PDF PubMed Scopus Google were on a of was in a and were for and for for and for by a These products of and for the and the for was using control G. Ward J.M. Gonzalez F.J. nuclear receptor is for of expression and lipid 2001; PubMed Scopus Google Scholar). 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In bile acid levels in FxrΔL and FxrΔIE mice were not significantly with in the of the Fxr-null mice, triglyceride and cholesterol levels of FxrΔL were significantly elevated with lipid levels of FxrΔIE were not significantly from These data that the presence of FXR in either liver or intestine is to normal bile acid concentrations but that FXR in liver is required for triglyceride and cholesterol was that the bile acid pool is increased in Fxr-null mice (12Kim I. Morimura K. Shah Y. Yang Q. Ward J.M. Gonzalez F.J. Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice.Carcinogenesis. 2007; 28: 940-946Crossref PubMed Scopus (272) Google Scholar, T. H. F. B. M. Kuipers F. of bile in farnesoid X intestinal bile salt absorption in the absence of bile Full Text Full Text PDF PubMed Scopus Google Scholar). the of FXR in liver and intestine to the bile acid pool of bile acids were from liver, and small intestine and for both bile acid levels and bile acid by Consistent with the bile acid pool was increased in Fxr-null mice in the bile acid pool was also in FxrΔL a increased bile acid pool was in FxrΔIE mice not The of the was in the Fxr-null mice in either the FxrΔL or FxrΔIE mice, that FXR in both liver and intestine to the bile acid pool size. the of to the increased bile acid pool bile acid were in more In of bile cholic acid acid and acid the bile acid was less of the bile acid and differences and Fxr-null were the bile acid in the bile acid pool was and in and Fxr-null mice, and in and FxrΔL mice, and and in and FxrΔIE mice, bile acids are in their (1Hofmann A.F. The continuing importance of bile acids in liver and intestinal disease.Arch. Intern. Med. 1999; 159: 2647-2658Crossref PubMed Scopus (632) Google the bile acids were was a in acid the bile in and FxrΔIE with their levels increased and in and FxrΔIE mice, with control The of these is in with the in the bile acid pool The acid was also increased in In the acid was not significantly in Fxr-null and FxrΔL mice and was in FxrΔIE mice with their was in acid levels in These that the in bile acid pool in the is to in and its a small of bile acids are in the the of bile acids are reabsorbed in the ileum (1Hofmann A.F. The continuing importance of bile acids in liver and intestinal disease.Arch. Intern. Med. 1999; 159: 2647-2658Crossref PubMed Scopus (632) Google Scholar). Bile acid was in to the increased bile acid pool was in bile acid the bile acids were owing to the actions of not was significantly increased in from FxrΔIE mice but not from Fxr-null or FxrΔL was a increased in and FxrΔIE mice with their were in bile acid the mechanistic basis for the increased bile acid pool in FxrΔL and FxrΔIE mice, expression was by using from liver and of FxrΔL and FxrΔIE to in Fxr-null mice, the of CYP7A1 mRNA expression was significantly increased in FxrΔL in CYP7A1 levels was in FxrΔIE mice was in CYP8B1 mRNA levels in either the FxrΔL or FxrΔIE mice was a expression in liver but not ileum of FxrΔL was a expression in ileum but not liver of FxrΔIE mRNA levels were significantly in ileum of FxrΔIE mice expression by GW4064 in the intestine-specific FXR-null was on from or of or intestine-specific Fxr-null mice with or GW4064 in and expression was in CYP7A1, and expression was in liver. are a to the expression of control with control the of FXR in regulating expression in liver and intestine, and control mice were either the FXR-selective agonist GW4064 or GW4064 induced and mRNA expression in of control mice but not FxrΔL mice and induced and in ileum of control mice but not FxrΔIE mice in FxrΔL CYP7A1 mRNA expression was repressed by In GW4064 not significantly CYP7A1 in FxrΔIE mice, expression was induced in FxrΔIE mice these data that FXR in intestine but not liver is required for repression of CYP7A1. CYP8B1 a of regulation with CYP7A1. GW4064 repressed CYP8B1 expression in of control mice, repression was to in FxrΔL mice In to CYP7A1, of FXR in intestine a effect on repression of CYP8B1 These data that CYP7A1 and CYP8B1 are regulated by with CYP7A1 repression more dependent on FXR in intestine and CYP8B1 repression more dependent on FXR in liver. The that intestinal FXR is required for repression of CYP7A1 is with the signaling a in CYP7A1 FGF15 was not induced by GW4064 in ileum of FxrΔIE mice but was induced in ileum of control and FxrΔL mice The of the signaling in regulating expression was by the expression of which is regulated by FGF15 A. Huang X. Bile acids expression and plasma levels via FXR-mediated signaling of 2006; PubMed Scopus Google Scholar, H.R. J. Edwards P.A. for FXR and in the repression of expression by bile Lipid Res. 2006; 47: Full Text Full Text PDF PubMed Scopus Google Scholar). mRNA levels were significantly by GW4064 in control and FxrΔL liver but not in liver of FxrΔIE mice These data provide evidence that FGF15 from the small intestine to the regulation of genes in response to GW4064 in liver. FGF15 on CYP7A1 and mice were with recombinant FGF15 or The regulation of CYP7A1 by FGF15 and in mice was with T. M. Moschetta A. Peng L. C.L. G. Jones S.A. B. Richardson J.A. et functions to bile acid Full Text Full Text PDF PubMed Scopus Google Scholar). FGF15 repressed CYP7A1 expression but not significantly affect CYP8B1 mRNA levels these the effect of GW4064 on CYP7A1 and CYP8B1 expression was in and CYP7A1 mRNA levels were increased in mice, CYP8B1 mRNA levels were elevated a more GW4064 repressed both CYP7A1 and CYP8B1 expression to a in in mice, GW4064 repressed CYP8B1 expression but not cause a in CYP7A1 mRNA these data that feedback repression of CYP7A1 is more regulated by the signaling is CYP8B1. The regulation of bile acid homeostasis by FXR is of In liver, FXR a of genes CYP7A1, and that bile acid pool and in intestine, FXR genes involved in bile acid and FGF15 B. Jones S.A. M.A. D.D. Moore C. Wilson et regulatory of the nuclear and represses bile acid 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M. K. Auwerx J. basis for feedback regulation of bile acid synthesis by nuclear 2000; Google Scholar, H. Zhang Y. Gonzalez F.J. Edwards P.A. FXR and in the and Lipid Res. 2006; 47: Full Text Full Text PDF PubMed Scopus Google Scholar, M. N. M. F.J. bile salt is by the farnesoid X acid 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, O. J. M. M. Farnesoid X receptor and bile are involved in regulation of the encoding the bile salt 2002; PubMed Scopus Google Scholar, S.R. The nuclear receptor for bile and J. 2006; PubMed Scopus Google Scholar). the of FXR in mice causes in bile acid homeostasis C.J. M. M. Ward J.M. G. Gonzalez F.J. of the nuclear receptor bile acid and lipid 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, G. M. Ward J.M. S.A. Gonzalez F.J. Sinal C.J. roles of farnesoid X X and receptor in bile acid Full Text Full Text PDF PubMed Scopus Google its importance in liver and intestine was not In the was using liver- and intestine-specific FXR-null These reveal that FXR in both liver and intestine to the regulation of bile acid homeostasis. the of FXR in either liver or intestine in the bile acid pool and these were not in the Fxr-null of FXR a in bile acid concentrations C.J. M. M. Ward J.M. G. Gonzalez F.J. of the nuclear receptor bile acid and lipid 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) that was not in either the FxrΔL or FxrΔIE these data of FXR in liver and intestine normal which is to pool was increased in FxrΔIE but not in Fxr-null and FxrΔL to in Fxr-null and FxrΔL mice with but not increased bile acid synthesis in Fxr-null mice, bile acid to small intestine was not increased but was C.J. M. M. Ward J.M. G. Gonzalez F.J. of the nuclear receptor bile acid and lipid 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) or G. M. Ward J.M. S.A. Gonzalez F.J. Sinal C.J. roles of farnesoid X X and receptor in bile acid Full Text Full Text PDF PubMed Scopus Google Scholar). The that bile acid is not in either Fxr-null or FxrΔL mice and is increased in FxrΔIE mice that the increased bile acid pool in FxrΔIE mice is to of bile acid synthesis to in bile acid the of the of of the bile to the increased bile acid in FxrΔIE The effect of the FXR agonist GW4064 in liver- and intestine-specific FXR-null mice was also and were induced by GW4064 in the of FxrΔIE but not FxrΔL Conversely, and FGF15 were induced by GW4064 in small intestine of FxrΔL but not FxrΔIE was that FXR represses CYP7A1 through the induction of FGF15 in intestine T. M. Moschetta A. Peng L. C.L. G. Jones S.A. B. Richardson J.A. et functions to bile acid Full Text Full Text PDF PubMed Scopus Google Scholar) and in liver B. Jones S.A. M.A. D.D. Moore C. Wilson et regulatory of the nuclear and represses bile acid 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M. K. Auwerx J. basis for feedback regulation of bile acid synthesis by nuclear 2000; Google Scholar). FGF15 and to CYP7A1 transcription through a mechanism that is not mice of either FGF15 or have elevated CYP7A1 expression T. M. Moschetta A. Peng L. C.L. G. Jones S.A. B. Richardson J.A. et functions to bile acid Full Text Full Text PDF PubMed Scopus Google Scholar, L. D. Y. S. Kim M. et for negative feedback regulation of bile acid 2002; Full Text Full Text PDF PubMed Scopus Google the of intestinal and liver FXR to the repression of CYP7A1 was not The of repression of CYP7A1 in FxrΔIE mice with GW4064 the evidence that FXR in the bile acid synthesis in the liver. The of FGF15 induction that hormone is for signaling from intestine to liver. Consistent with FXR-mediated repression of which is also by FGF15 A. Huang X. Bile acids expression and plasma levels via FXR-mediated signaling of 2006; PubMed Scopus Google Scholar, H.R. J. Edwards P.A. for FXR and in the repression of expression by bile Lipid Res. 2006; 47: Full Text Full Text PDF PubMed Scopus Google was in FxrΔIE but not FxrΔL FXR-mediated repression of CYP7A1 was in the FxrΔL mice the of These data that induction of levels is not for FXR-mediated repression of CYP7A1. that of the effect of FXR on CYP7A1 transcription is mediated by induction of FGF15 in intestine. are that in the CYP7A1 data from these intestinal FGF15 CYP7A1, the FxrΔL but not the FxrΔIE mice have increased CYP7A1 mRNA The regulation of via intestinal is that normal physiological the bile acid to the distal small intestine the end of the FXR in the ileum and to the liver for is not to a induction of in the liver of FxrΔIE mice, liver FXR and transcription are of in FxrΔIE mice, which using a FXR to a bile acid pool size. In addition, is to that the mice, the FxrΔIE mice FGF15, in the This FGF15 to CYP7A1 transcription in the of FXR response in liver. the with mice, is also that the FxrΔIE mice have a response that CYP7A1 expression in the absence of the normal of intestinal FXR to the regulation of bile acid is the intestine-specific FXR-null mice a increased bile acid pool not have increased CYP7A1 expression. is that the pathway for bile acid synthesis is in the intestine FXR-null to the bile acid a bile acid pool in FxrΔIE mice is to in pool that in bile acid pool is more to the classic pathway to the not in or which are the products of the pathway in FxrΔIE mice, with the molecular basis for is not to the FXR-selective which the presence of GW4064 in liver is by the induction of in and FxrΔIE mice, the of on FXR in intestine liver to the of This of in liver to of the importance of FXR-mediated induction of and genes in liver in the feedback regulation of CYP7A1. FXR also in the feedback repression of CYP8B1. of was the regulation of CYP7A1 and CYP8B1 by repression of CYP7A1 was more by of FXR in intestine, repression of CYP8B1 was more to of FXR in liver. of these data is that CYP7A1 is regulated more by the pathway in intestine and CYP8B1 is more to repression via FXR activation in liver. In of CYP7A1 was repressed by of FGF15, CYP8B1 was CYP8B1 was repressed by FXR activation in mice, CYP7A1 was expression of CYP7A1 increased in mice, CYP8B1 mRNA levels increased less that CYP8B1 mRNA levels were significantly increased in the mice, that CYP8B1 expression is by FGF15, in the was that of with the bile acid which levels of of induced CYP7A1 expression but not CYP8B1 A. E. S. I. C. regulation of bile acid synthesis in importance of for regulation of Res. PubMed Scopus Google Scholar, T. C. B. M. intestinal a and modulates bile acid synthesis in Intern. Med. 2006; PubMed Scopus Google Scholar). repression of CYP7A1 by bile acids was in of mice of the FGF15 receptor CYP8B1 repression was not S. T. A. J. Y. Y. negative feedback of bile acid synthesis in mice Clin. Invest. PubMed Scopus Google Scholar). with data in these that the CYP7A1 is more CYP8B1 to repression by from the intestine. The molecular basis for regulation and its physiological to In and intestine-specific Fxr-null mice were and to but complementary roles for FXR in liver and intestine in regulating bile acid homeostasis. This the evidence that FXR in intestine bile acid synthesis in liver and a for FGF15 to liver CYP7A1. differences were in the feedback repression of CYP7A1 and CYP8B1. The tissue-specific Fxr-null mice for of the tissue-specific roles of FXR in bile acid metabolism and and This was by of and and the A. The and L. for the and and Gerard for in recombinant FGF15 cholic acid acid farnesoid X receptor acid acid acid