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

被引:471
作者
Kim, Insook
Ahn, Sung-Hoon
Inagaki, Takeshi
Choi, Mihwa
Ito, Shinji
Guo, Grace L.
Kliewer, Steven A.
Gonzalez, Frank J. [1 ]
机构
[1] NCI, Natl Inst Hlth, Met Lab, Bethesda, MD 20892 USA
[2] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA
关键词
FXR; FGF15; CYP7A1; CYP8B1; liver-specific FXR null mice; intestine-specific FXR null mice;
D O I
10.1194/jlr.M700330-JLR200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:2664 / 2672
页数:9
相关论文
共 40 条
[1]   Feedback regulation of bile acid synthesis in human liver:: Importance of HNF-4α for regulation of CYP7A1 [J].
Abrahamsson, A ;
Gustafsson, U ;
Ellis, E ;
Nilsson, LM ;
Sahlin, S ;
Björkhem, I ;
Einarsson, C .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2005, 330 (02) :395-399
[2]   Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor [J].
Ananthanarayanan, M ;
Balasubramanian, N ;
Makishima, M ;
Mangelsdorf, DJ ;
Suchy, FJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (31) :28857-28865
[3]   Activation of the farnesoid X receptor improves lipid metabolism in combined hyperlipidemic hamsters [J].
Bilz, S ;
Samuel, V ;
Morino, K ;
Savage, D ;
Choi, CS ;
Shulman, GI .
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 2006, 290 (04) :E716-E722
[4]   The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice [J].
Cariou, B ;
van Harmelen, K ;
Duran-Sandoval, D ;
van Dijk, TH ;
Grefhorst, A ;
Abdelkarim, M ;
Caron, S ;
Torpier, G ;
Fruchart, JC ;
Gonzalez, FJ ;
Kuipers, F ;
Staels, B .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (16) :11039-11049
[5]   Identification of a hormonal basis for gallbladder filling [J].
Choi, Mihwa ;
Moschetta, Antonio ;
Bookout, Angie L. ;
Peng, Li ;
Umetani, Michihisa ;
Holmstrom, Sam R. ;
Suino-Powell, Kelly ;
Xu, H. Eric ;
Richardson, James A. ;
Gerard, Robert D. ;
Mangelsdorf, David J. ;
Kliewer, Steven A. .
NATURE MEDICINE, 2006, 12 (11) :1253-1255
[6]  
Claudel T, 2002, J CLIN INVEST, V109, P961
[7]   A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis [J].
Goodwin, B ;
Jones, SA ;
Price, RR ;
Watson, MA ;
McKee, DD ;
Moore, LB ;
Galardi, C ;
Wilson, JG ;
Lewis, MC ;
Roth, ME ;
Maloney, PR ;
Willson, TM ;
Kliewer, SA .
MOLECULAR CELL, 2000, 6 (03) :517-526
[8]   Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicity [J].
Guo, GL ;
Lambert, G ;
Negishi, M ;
Ward, JM ;
Brewer, HB ;
Kliewer, SA ;
Gonzalez, FJ ;
Sinal, CJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (46) :45062-45071
[9]   Bile acids decrease hepatic paraoxonase 1 expression and plasma high-density lipoprotein levels via FXR-mediated signaling of FGFR4 [J].
Gutierrez, A ;
Ratliff, EP ;
Andres, AM ;
Huang, XQ ;
McKeehan, WL ;
Davis, RA .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2006, 26 (02) :301-306
[10]   Hepatocyte nuclear factor 4α (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis [J].
Hayhurst, GP ;
Lee, YH ;
Lambert, G ;
Ward, JM ;
Gonzalez, FJ .
MOLECULAR AND CELLULAR BIOLOGY, 2001, 21 (04) :1393-1403