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J. Biol. Chem. 275 (20): 15482-15489

© 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

J Biol Chem, Vol. 275, Issue 20, 15482-15489, May 19, 2000

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

Chundong YuDagger §, Fen WangDagger , Mikio KanDagger , Chengliu JinDagger , Richard B. JonesDagger , Michael Weinstein, Chu-Xia Deng, and Wallace L. McKeehanDagger ||

From the Department of Biochemistry and Biophysics, Texas A&M University and Dagger  Center for Cancer Biology and Nutrition, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas 77030-3303, the § Graduate School of Biomedical Sciences, University of Texas-Houston Health Science Center, Houston, Texas 77030, and the  Genetics of Development and Disease Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892

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 7alpha -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 alpha , may mediate the negative regulation of cholesterol- and bile acid-controlled liver cholesterol 7alpha -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.

* This work was supported by Public Health Service Grants DK35310 and DK47039 from the NIDDK, National Institutes of Health and Grant CA59971 from the NCI, National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| To whom correspondence should be addressed: Inst. of Biosciences and Technology, 2121 W. Holcombe Blvd., Houston, TX 77030-3303. Tel.: 713-677-7522; Fax: 713-677-7512; E-mail: wmckeeha@ibt.tamu.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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