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J Biol Chem, Vol. 275, Issue 20, 15482-15489, May 19, 2000
From the Department of Biochemistry and Biophysics, Texas A&M
University and 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 (
Elevated Cholesterol Metabolism and Bile Acid Synthesis in Mice
Lacking Membrane Tyrosine Kinase Receptor FGFR4*
§,,,,,
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
/)
mice exhibited depleted gallbladders, an elevated bile acid pool and elevated excretion of bile acids. Cholesterol- and bile acid-controlled liver cholesterol 7
-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
, may mediate the negative regulation of cholesterol- and bile
acid-controlled liver cholesterol 7-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.
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