Elevated Cholesterol Metabolism and Bile Acid Synthesis in Mice Lacking Membrane Tyrosine Kinase Receptor FGFR4

Abstract

Heparan sulfate-regulated transmembrane tyrosine kinase receptor FGFR4 is the major FGFR isotype in mature hepatocytes. Fibroblast growth factor has been implicated in the definition of liver from foregut endoderm where FGFR4 is expressed and stimulation of hepatocyte DNA synthesis in vitro. Here we show that livers of mice lacking FGFR4 exhibited normal morphology and regenerated normally in response to partial hepatectomy. However, the FGFR4 (−/−) mice exhibited depleted gallbladders, an elevated bile acid pool and elevated excretion of bile acids. Cholesterol- and bile acid-controlled liver cholesterol 7α-hydroxylase, the limiting enzyme for bile acid synthesis, was elevated, unresponsive to dietary cholesterol, but repressed normally by dietary cholate. Expression pattern and cholate-dependent, cholesterol-induced hepatomegaly in the FGFR4 (−/−) mice suggested that activation of receptor interacting protein 140, a co-repressor of feed-forward activator liver X receptor α, may mediate the negative regulation of cholesterol- and bile acid-controlled liver cholesterol 7α-hydroxylase transcription by FGFR4 and cholate. The results demonstrate that transmembrane sensors interface with metabolite-controlled transcription networks and suggest that pericellular matrix-controlled liver FGFR4 in particular may ensure adequate cholesterol for cell structures and signal transduction. Heparan sulfate-regulated transmembrane tyrosine kinase receptor FGFR4 is the major FGFR isotype in mature hepatocytes. Fibroblast growth factor has been implicated in the definition of liver from foregut endoderm where FGFR4 is expressed and stimulation of hepatocyte DNA synthesis in vitro. Here we show that livers of mice lacking FGFR4 exhibited normal morphology and regenerated normally in response to partial hepatectomy. However, the FGFR4 (−/−) mice exhibited depleted gallbladders, an elevated bile acid pool and elevated excretion of bile acids. Cholesterol- and bile acid-controlled liver cholesterol 7α-hydroxylase, the limiting enzyme for bile acid synthesis, was elevated, unresponsive to dietary cholesterol, but repressed normally by dietary cholate. Expression pattern and cholate-dependent, cholesterol-induced hepatomegaly in the FGFR4 (−/−) mice suggested that activation of receptor interacting protein 140, a co-repressor of feed-forward activator liver X receptor α, may mediate the negative regulation of cholesterol- and bile acid-controlled liver cholesterol 7α-hydroxylase transcription by FGFR4 and cholate. The results demonstrate that transmembrane sensors interface with metabolite-controlled transcription networks and suggest that pericellular matrix-controlled liver FGFR4 in particular may ensure adequate cholesterol for cell structures and signal transduction. fibroblast growth factor FGF receptor cholesterol 7α-hydroxylase receptor interacting protein 140 liver X receptor 3-hydroxy-3-methylglutaryl-CoA partial hepatectomy reverse transcriptase-polymerase chain reaction ileal sodium-dependent bile acid transporter intestinal bile acid-binding protein ribonuclease protection bromodeoxyuridine oxysterol 7α-hydroxylase retinoid X receptor sterol 27-hydroxylase farnesoid X receptor nucleotide(s) phosphate-buffered saline The fibroblast growth factor (FGF)1 tyrosine kinase signaling complex is an intrinsic mediator of cell to cell communication in tissue remodeling in development and cellular homeostasis in adult organs (1.Mason I.J. Cell. 1994; 78: 547-552Abstract Full Text PDF PubMed Scopus (525) Google Scholar, 2.McKeehan W.L. Wang F. Kan M. Prog. Nucleic Acids Res. Mol. Biol. 1998; 59: 135-176Crossref PubMed Scopus (361) Google Scholar). The FGF receptor kinase family consists of an extensive repertoire of alternately spliced products of four genes (fgfr1 to fgfr4), which are expressed in development in a temporal- and spatially specific mode (3.Xu X. Weinstein M. Li C. Deng C. Cell Tissue Res. 1999; 296: 33-43Crossref PubMed Scopus (127) Google Scholar) and in adult tissues in a cell type-specific mode (2.McKeehan W.L. Wang F. Kan M. Prog. Nucleic Acids Res. Mol. Biol. 1998; 59: 135-176Crossref PubMed Scopus (361) Google Scholar). Disruption of thefgfr1 and fgfr2 genes in mice disrupt development, exhibit global proliferation defects, and are embryonic lethal (4.Deng C.X. Wynshaw-Boris A. Shen M.M. Daugherty C. Ornitz D.M. Leder P. Genes Dev. 1994; 8: 3045-3057Crossref PubMed Scopus (632) Google Scholar, 5.Xu X. Weinstein M. Li C. Naski M. Cohen R.I. Ornitz D.M. Leder P. Deng C. Development. 1998; 125: 753-765Crossref PubMed Google Scholar). Mice in which fgfr3 was disrupted are viable, but exhibit severe skeletal dysplasias due to overgrowth of long bones, which is a consequence of loss of restraints on growth of chondrocytes during endochondral ossification (6.Colvin J.S. Bohne B.A. Harding G.W. McEwen D.G. Ornitz D.M. Nat. Genet. 1996; 12: 390-397Crossref PubMed Scopus (753) Google Scholar, 7.Deng C. Wynshaw-Boris A. Zhou F. Kuo A. Leder P. Cell. 1996; 84: 911-921Abstract Full Text Full Text PDF PubMed Scopus (912) Google Scholar). FGF-1, FGF-2, and FGF-8 have been implicated in definition of the liver from foregut endoderm where FGFR4 is expressed (8.Jung J. Zheng M. Goldfarb M. Zaret K.S. Science. 1999; 284: 1998-2003Crossref PubMed Scopus (607) Google Scholar). However, disruption of fgfr4 in the mouse germline resulted in no overt abnormalities (9.Weinstein M. Xu X. Ohyama K. Deng C.X. Development. 1998; 125: 3615-3623Crossref PubMed Google Scholar). All four fgfr genes are expressed in adult liver (10.Kan M. McKeehan W.L. Strain A. Diehl A. Liver Growth and Repair. 9. Chapman & Hall, London1998: 240-260Crossref Google Scholar), but only FGFR4 is expressed in mature hepatocytes (11.Kan M. Wu X. Wang F. McKeehan W.L. J. Biol. Chem. 1999; 274: 15947-15952Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar). External administration of FGF-7 and FGF-18, or expression of FGF-18 under control of liver specific-promoters, elicits hyperplasia in the liver (12.Housley R.M. Morris C.F. Boyle W. Ring B. Biltz R. Tarpley J.E. Aukerman S.L. Devine P.L. Whitehead R.H. Pierce G.F. J. Clin. Invest. 1994; 94: 1764-1777Crossref PubMed Scopus (264) Google Scholar, 13.Hu M.C. Qiu W.R. Wang Y.P. Hill D. Ring B.D. Scully S. Bolon B. DeRose M. Luethy R. Simonet W.S. Arakawa T. Danilenko D.M. Mol. Cell. Biol. 1998; 18: 6063-6074Crossref PubMed Scopus (108) Google Scholar). FGF-1 and FGF-7 elicit DNA synthesis in primary liver cell cultures enriched in hepatocytes (14.Kan M. Huang J.S. Mansson P.E. Yasumitsu H. Carr B. McKeehan W.L. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 7432-7436Crossref PubMed Scopus (166) Google Scholar, 15.Itoh T. Suzuki M. Mitsui Y. Biochem. Biophys. Res. Commun. 1993; 192: 1011-1015Crossref PubMed Scopus (19) Google Scholar). To determine whether FGFR4 plays a role in liver in vivo, we examined the morphology of the liver and associated organs infgfr4 − /fgfr4 − mice, including the compensatory growth response after partial hepatectomy. Here we report no differences in liver architecture and kinetics or extent of restoration of liver mass between wild-type andfgfr4−/fgfr4 − animals. However, examination of liver-associated organs revealed a small, depleted gallbladder in the FGFR4-deficient mice that prompted an analysis of cholesterol and bile acid metabolism. The results revealed that the FGFR4 deficiency caused a significant elevation of the excreted and total bile acid pools. Elevation of bile acid pools were coincident with constitutively elevated expression of Cyp7a, the limiting enzyme in the classical pathway for bile acid synthesis (16.Russell D.W. Setchell K.D. Biochemistry. 1992; 31: 4737-4749Crossref PubMed Scopus (656) Google Scholar), and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting step in cholesterol synthesis (17.Goldstein J.L. Brown M.S. Nature. 1990; 343: 425-430Crossref PubMed Scopus (4537) Google Scholar). The FGFR4 knockout mice exhibited a cholate-dependent, cholesterol-induced hepatomegaly. Analysis of gene expression in the hepatomegalic livers of the mutant mice suggested points where both FGFR4 and bile acids exert negative controls on liver bile acid synthesis. These results implicate the pericellular matrix-controlled FGFR4 kinase complex in hepatocytes in control of cholesterol metabolism and bile acid synthesis in a physiological setting. Disruption of the mouse fgfr4locus was carried out in 129 Sv strain-derived ES cells as described (9.Weinstein M. Xu X. Ohyama K. Deng C.X. Development. 1998; 125: 3615-3623Crossref PubMed Google Scholar). Wild-type 129 Sv mice were obtained from the Jackson Laboratory. FGFR4 (+/−) mice were generated by crossing FGFR4 (−/−) mice with wild-type 129 Sv mice, or by further crossing FGFR4 (+/−) with FGFR4 (−/−) mice. Only mice 7–8 weeks old were used in the study. Male mice were used for partial hepatectomy (PH)-induced liver regeneration experiments, and female mice were used in all other protocols. Mice were maintained in 12-h light/12-h dark cycles and were given free access to food and water. Standard rodent chow containing 0.02% (w/w) cholesterol and the standard chow supplemented with 2% (w/w) cholesterol or both 2% (w/w) cholesterol and 2% (w/w) sodium cholate was obtained from Alief Purina Feed Store, Inc. (Alief, TX). Two to four mice were employed for each experimental group, as described in the specific figure legends. After the mice were weighed, anesthetized, and exsanguinated, the livers or other tissues were harvested at 10:00 a.m., except that of the mice used in the PH-induced liver regeneration, which were harvested at the times indicated. All procedures were performed in accordance with the Institutional Animal Care and Use Committee at the Institute of Biosciences and Technology, Texas A&M University System Health Science Center. Full-length murine Cyp7a (pCMV-mCyp7a), Cyp7b (phct1), and Cyp27a (pCMV-m27OH) cDNAs were gifts from Dr. David W. of Texas TX). Full-length murine and cDNAs were gifts from Dr. David J. of Texas TX). was by the reverse chain reaction from mouse liver and FGFR4 was by from mouse liver and was by from mouse liver and was by from mouse liver and ileal sodium-dependent bile acid transporter was by from mouse and intestinal bile acid-binding protein was from mouse and All products of were by and enzyme to of the cDNAs described which been were by or the The of and the were as and and Cyp7a, and Cyp7b and and reductase, and and and and and and and was from livers or ileal tissue with the System and specific were by ribonuclease protection the of liver or ileal was with of specific and in the reaction After with products were on by of protection products was from the of a DNA reaction to the protection The of each was a The of between was by of the of the in each were expressed in to the of expression in wild-type mice on standard which was a of were in containing sodium and and The protein was the protein total of of protein was to to with from Dr. David W. and with to was carried out the acids were the Acids To determine bile acid the from mice were weighed, and a of was and in of at for The was and of were for to with a The bile acid was The of and bile acid were used to the of bile acid excretion of The total bile acid pool was as bile acid of the the the and After the mice were weighed, anesthetized, and exsanguinated, the organs were and in of at for The was of for were to with and were to with acids were and the pool was expressed as of bile of To cholesterol of liver was and in of with of at for The was and the cholesterol in the was a The cholesterol was and expressed as of of liver Liver tissues were in Tissue a of and in to standard were and with and of of the and was performed on mice at 10:00 Two to of the for of of bromodeoxyuridine was livers were and at in liver was with an and an hepatocytes were and was expressed as the of the of hepatocytes in four or are expressed as the standard with the of described in the to The of differences between was the examination of the liver revealed no abnormalities in the cellular and of in wild-type and FGFR4-deficient (−/−) mice. The knockout exhibited normal including and and hepatectomy was performed on both FGFR4 (−/−) mice and FGFR4 mice, and both DNA synthesis and restoration of liver mass was for to after the DNA synthesis at the and both the and extent of of liver mass were in both wild-type and mutant mice FGFR4 is in compensatory growth of the liver in response to loss of of the liver or is for by other of livers for partial we that the of FGFR4 (−/−) mice, of were and on of from FGFR4 mice The was maintained in mice a exhibited an in total analysis revealed no in gallbladder morphology and between mutant and wild-type mice Analysis of and as as from both and female FGFR4 FGFR4 and FGFR4 mice, revealed that bile acids were elevated in FGFR4-deficient mice and of the from wild-type and FGFR4-deficient mice no on the bile acid excretion suggested that an in bile acid metabolism and was the of the in mutant mice, a in architecture and of the has been that of bile acid synthesis, by bile acid by intestinal gallbladder and a in gallbladder P. A. J. 1994; Google Scholar, P. A. J. Clin. Invest. PubMed Scopus Google Scholar). the bile acid pool by an in FGFR4 mice on a cholesterol W. B.A. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar), the on the elevated pool in the FGFR4-deficient FGFR4 and FGFR4 (−/−) exhibited a pool of of which to on the pool in FGFR4 (−/−) mice was times that of normal at and to pools were in normal mice. which an in the bile acid pools of both normal M. S.L. 1998; PubMed Scopus Google Scholar) and mutant mice, the pool in FGFR4 (−/−) mice to times of that of wild-type adult of at in mutant mice to after and that an elevation of bile acid pools in the mice to of for of bile acids in the and liver P. D. J. Biol. Chem. 1990; Full Text PDF PubMed Google Scholar, Setchell K.D. Res. PubMed Scopus Google Scholar) and the acid pathway for synthesis of bile acids M. R. D.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Expression of for and transcription is and repressed by bile T. Y. P. M. Y. K. T. H. Biochem. J. 1998; PubMed Scopus Google Scholar, Biochem. Biophys. Res. Commun. 1996; PubMed Scopus Google Scholar), was and in mature FGFR4-deficient mice and These suggested a role of FGFR4 in bile acid metabolism at the of synthesis in the Elevation of bile acids may from from cholesterol, or of cholesterol synthesis or in the are at transcription by and products both liver M. J. Res. 1992; Full Text PDF PubMed Google Scholar). of reductase, the rate-limiting enzyme in cholesterol in on standard rodent chow cholesterol which is repressed by and are M.S. J.L. J. Res. Full Text PDF PubMed Google Scholar), was elevated by in the FGFR4 (−/−) but to in both FGFR4 and FGFR4 (−/−) a Cyp7a, which cholesterol is the rate-limiting enzyme in the classical of bile acid synthesis (16.Russell D.W. Setchell K.D. Biochemistry. 1992; 31: 4737-4749Crossref PubMed Scopus (656) Google Scholar). Cyp7a is at transcription in a feed-forward mode by oxysterol of cholesterol J.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), and in mode by bile acids. The expression of liver Cyp7a was elevated by in FGFR4 (−/−) mice with wild-type analysis revealed that the elevation of the of protein was to the in the cholesterol Cyp7a expression by in wild-type mice, the to the elevated of Cyp7a expression in FGFR4 (−/−) mice the elevated Cyp7a in the FGFR4-deficient was as a consequence of the cholesterol is a of Cyp7a transcription S. D.W. J. Biol. Chem. 1990; Full Text PDF PubMed Google Scholar). The of cholate to the cholesterol chow revealed that for bile of Cyp7a expression were and to These results suggest that FGFR4 bile acid synthesis of Cyp7a expression and that Cyp7a is constitutively elevated in FGFR4 and FGFR4 (−/−) mice on a cholesterol exhibited no significant in liver or liver cholesterol with a containing both 2% (w/w) cholesterol and cholate that repressed Cyp7a liver cholesterol exhibited an of times in both wild-type and mutant mice. the liver in the FGFR4-deficient weeks on the and was times wild-type livers after and of cholate no The hepatomegaly was by the hepatocytes in of livers from FGFR4 (−/−) mice analysis of DNA synthesis by of that the hepatomegaly in FGFR4 (−/−) mice was due to hepatocyte an in hepatocyte in FGFR4 knockout mice on cholesterol and cholate morphology of livers from FGFR4 and FGFR4 (−/−) mice standard chow or chow containing 2% cholesterol and 2% cholate for of livers from FGFR4 and FGFR4 (−/−) mice. from livers of mice 2% cholesterol and 2% cholate for were and with and is cholesterol-induced hepatomegaly on dietary and in the FGFR4-deficient mice, which to of of Cyp7a is M. Setchell J.E. J. D.W. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar), the acid pathway of bile acid synthesis by and of from cholesterol M. R. D.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Res. 1992; Full Text PDF PubMed Google Scholar). the pathway is by bile acids the classical pathway M. D.W. 1998; PubMed Scopus Google Scholar). examined expression of cholesterol and oxysterol 7α-hydroxylase rate-limiting of the acid protection analysis revealed no between expression of Cyp27a or Cyp7b between FGFR4 and FGFR4 (−/−) mice on standard However, Cyp27a was repressed as in as in wild-type mice on the a in Cyp27a in the mutant mice cholesterol cholate. in Cyp7b expression was under of the The of Cyp27a in of FGFR4 under where Cyp7a is repressed may to the hepatomegaly in the FGFR4-deficient mice. The hepatomegalic in FGFR4 (−/−) mice by the was to that by cholesterol in mice of the gene for the oxysterol receptor and transcription factor W. B.A. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). no in the expression of or in all described in wild-type and mice However, a for differences in expression of of in the wild-type and FGFR4 knockout mice revealed that expression of the and co-repressor was to the dietary Expression of was by in wild-type mice cholesterol, but elevated in mice both cholesterol and cholate. in FGFR4-deficient on standard chow was of that in wild-type the cholesterol caused no further but expression by in the mutant cholate was to the cholesterol has been to a of activation by X receptor as as receptor with or receptor K.S. Mol. Cell. 1998; PubMed Scopus Google Scholar). results suggest in to of Cyp7a expression negative bile acid response at bile acid products Cyp7a activation of a co-repressor of the oxysterol receptor and feed-forward activator The of in FGFR4-deficient by the of cholate may to the cholesterol-induced hepatomegaly in the mutant animals. the constitutively of normally an co-repressor of a for the elevated Cyp7a expression and elevated bile acid synthesis in the FGFR4 (−/−) mice on standard has major the regulation of of cholesterol to bile acids. knockout of Cyp7a, the rate-limiting enzyme of the classical bile acid pathway caused in bile acid synthesis, and liver in weeks in of mice. The other of mice to the normal in the The by dietary with and which weeks after S. M. J. D.W. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). the compensatory of the or pathway of bile acid synthesis The pathway is by sterol that cholesterol to Disruption of the gene for sterol 27-hydroxylase gene in mice resulted in bile acid synthesis and excretion of bile acids to of normal coincident with elevation of transcription of Cyp7a by due to of bile was elevated by due to of cholesterol by elevated Cyp7a H. A. A. S. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). The transcription has been as an oxysterol receptor that the gene in a feed-forward disruption of the in mice on a in bile acid pool However, the knockout mice were cholesterol, to Cyp7a and cholesterol in the liver to hepatomegaly W. B.A. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). farnesoid X receptor has been as a bile acid bile acid synthesis by of liver Cyp7a at transcription and in the by activation of M. H. R.M. A. K.D. B. Science. 1999; 284: PubMed Scopus Google Scholar, Science. 1999; 284: PubMed Scopus Google Scholar). Disruption of the gene is to in elevated of excreted bile of bile acid elevation of Cyp7a due to loss of regulation and of due to cholesterol D.W. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). These have revealed the metabolite-controlled networks that the of but cholesterol and in a physiological Here we implicate the transmembrane tyrosine kinase FGFR4 in control of cholesterol metabolism to bile acids by gene disruption in mice. to the Cyp7a and Cyp27a knockout mice, both the excreted and total bile acid pools are that FGFR4 normally a negative control on cholesterol metabolism to bile which is by disruption of in and the elevated bile acid in the FGFR4-deficient mice was the elevation of bile acid pools was significant to of intestinal and and of ileal bile acids by elevation of bile acid Cyp7a, and reductase, a in the total bile acid pool J. Clin. Invest. PubMed Scopus Google Scholar, J. 1996; PubMed Scopus Google Scholar). The normal of Cyp7a expression in the FGFR4-deficient mice to dietary bile acids an in the bile regulation in which the bile acid receptor has been the of knockout mice is to that which we for FGFR4-deficient mice, the of negative control by FGFR4 and to mediate or for the cholesterol chow synthesis by the of rate-limiting cholesterol to for metabolism and the of the bile acid pool that normally and Y. J. J. Clin. Invest. PubMed Scopus Google Scholar). the FGFR4-deficient mice, we an elevation of with the elevation of bile acid pools and the elevation of and cholesterol Cyp7a by feed-forward the other elevation of Cyp7a and to bile acids elevated of cholesterol FGFR4 is normally a of reductase, of was no in the dietary cholesterol-induced of in the FGFR4-deficient animals. Cyp7a elevated under the dietary that repressed reductase, the elevation of Cyp7a expression as a consequence of cholesterol synthesis was The elevation of in the FGFR4-deficient mice is a consequence of cholesterol due to bile acid synthesis. a negative role of FGFR4 on the acid pathway of bile acid synthesis was out the elevated bile acid pools in FGFR4 (−/−) mice was in mice at a Cyp7b and of the pathway is M. R. D.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). demonstrate that FGFR4 a negative control on cholesterol metabolism and bile acid synthesis in liver at the of expression of Cyp7a that for in and response have been for Cyp7a 1998; PubMed Scopus Google Scholar). of Cyp7a expression are for negative by the FGFR4 are the oxysterol receptor J.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), which in with which has been to in the of Cyp7a and of a cholesterol in the W. B.A. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). both FGFR4 knockout and normal mice dietary cholesterol, the of 2% (w/w) sodium cholate to the cholesterol chow the hepatomegalic described in (−/−) mice only the cholesterol W. B.A. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). in mice with elevated bile acid synthesis in of dietary cholate to the of both and the bile of bile acid synthesis. The cholate-dependent, cholesterol-induced hepatomegaly in the FGFR4 knockout mice was coincident with a in expression of a of transcription K.S. Mol. Cell. 1998; PubMed Scopus Google Scholar). The was a of expression in the knockout mice to in normal mice on both the and cholesterol that FGFR4 may bile acid synthesis expression of the co-repressor The elevation of expression by dietary cholate suggested a bile regulation at the feed-forward of cholesterol in to of Cyp7a in the gene M. H. R.M. A. K.D. B. Science. 1999; 284: PubMed Scopus Google Scholar). the expression of wild-type in the of dietary by the of M.S. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar) between bile and a transcription both of which wild-type mice, bile with an transcription factor for a which activation The of FGFR4 activation by which has a on results a and of regulation of Cyp7a transcription and bile acid synthesis that the of study. results show that a transmembrane signaling which cell to cell communication and in the tissue is to the metabolite-controlled that cholesterol and bile acid is that the FGFR complex cholesterol, bile and is that the pericellular matrix-controlled FGFR kinase complex in hepatocytes in the tissue that for a in liver cholesterol and metabolism in for liver cells or for the C. J. Res. 1996; Full Text PDF PubMed Google Scholar). The liver response to by and cholesterol and coincident with of Cyp7a C. J. Res. 1996; Full Text PDF PubMed Google Scholar). Liver Cyp7a and are after partial hepatectomy and to the response K. K. S. H. S. M. Res. PubMed Scopus Google Scholar). cholesterol has been implicated in an of signaling including M. J. R. F. K. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), of signaling Science. 1996; 274: PubMed Scopus Google Scholar), and of protein A. J. M. Brown J. Cell Biol. 1999; PubMed Scopus Google Scholar). in fgfr genes other fgfr4 in constitutively signaling which a of abnormalities M.C. Ornitz D.M. 1998; PubMed Google Scholar). deficiency or of FGFR4 may in cholesterol and bile acid suggest the signaling complex as a for or in of cholesterol and bile acid metabolism. FGFR4 knockout mice and mice FGFR4 in the liver for of cholesterol and bile acid Dr. D. W. for the murine Cyp7a, and Cyp27a cDNAs and Dr. D. J. for murine and and Kan for