論文

査読有り
2007年12月

Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine

JOURNAL OF LIPID RESEARCH
  • Insook Kim
  • ,
  • Sung-Hoon Ahn
  • ,
  • Takeshi Inagaki
  • ,
  • Mihwa Choi
  • ,
  • Shinji Ito
  • ,
  • Grace L. Guo
  • ,
  • Steven A. Kliewer
  • ,
  • Frank J. Gonzalez

48
12
開始ページ
2664
終了ページ
2672
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1194/jlr.M700330-JLR200
出版者・発行元
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

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 intestinespecific FXR-null models. FXR deficiency in either liver (Fxr Delta(L)) or intestine (Fxr Delta(IE)) increased bile acid pool size. Treatment with the FXR-selective agonist GW4064 significantly repressed CYP7A1 in Fxr Delta(L) mice but not Fxr Delta(IE) 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.

Web of Science ® 被引用回数 : 351

リンク情報
DOI
https://doi.org/10.1194/jlr.M700330-JLR200
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000251041500015&DestApp=WOS_CPL
ID情報
  • DOI : 10.1194/jlr.M700330-JLR200
  • ISSN : 0022-2275
  • Web of Science ID : WOS:000251041500015

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