Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4

Chundong Yu, Fen Wang, Mikio Kan, Chengliu Jin, Richard B. Jones, Michael Weinstein, Chu Xia Deng, Wallace L. McKeehan

Research output: Contribution to journalArticle

285 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)15482-15489
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number20
DOIs
StatePublished - May 19 2000
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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