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00胆汁酸合成的级联调节反应

Molecular Cell,Vol.6,517–526,September,2000,Copyright ©2000by Cell Press

A Regulatory Cascade of the Nuclear Receptors FXR,SHP-1,and LRH-1Represses Bile Acid Biosynthesis

of the nuclear receptor superfamily of ligand-activated transcription factors (Chiang,1998;Gustafsson,1999;Russell,1999).Recently,two nuclear receptors,the liver X receptor ␣(LXR ␣;NR1H3)(Apfel et al.,1994;Willy et al.,1995)and farnesoid X receptor (FXR;NR1H4)Bryan Goodwin,*Stacey A.Jones,*Roger R.Price,*Michael A.Watson,*David D.McKee,*

Linda B.Moore,*Cristin Galardi,*Joan G.Wilson,†Michael C.Lewis,†Matthew E.Roth,§

Patrick R.Maloney,‡Timothy M.Willson,‡(Forman et al.,1995;Seol et al.,1995),were implicated and Steven A.Kliewer*

in the feedforward and feedback regulation of CYP7A1,*Department of Molecular Endocrinology respectively (Peet et al.,1998;Russell,1999).Both LXR ␣†Department of Metabolic Diseases and FXR are abundantly expressed in the liver and ‡Department of Medicinal Chemistry

bind to their cognate hormone response elements as Glaxo Wellcome Research and Development heterodimers with the 9-cis retinoic acid receptor Research Triangle Park,North Carolina 27709RXR (Mangelsdorf and Evans,1995).LXR ␣is activated §CuraGen Corporation

by the cholesterol derivative 24,25(S )-epoxycholesterol New Haven,Connecticut 06511

and binds to a response element in the CYP7A1pro-moter (Lehmann et al.,1997).Mice lacking LXR ␣do not induce CYP7A1expression in response to cholesterol Summary

feeding (Peet et al.,1998).Moreover,these animals ac-cumulate massive amounts of cholesterol in their livers when fed a high cholesterol diet.These data establish Bile acids repress the transcription of cytochrome LXR ␣as the cholesterol sensor responsible for feedfor-P4507A1(CYP7A1),which catalyzes the rate-limiting ward regulation of CYP7A1expression.

step in bile acid biosynthesis.Although bile acids acti-Bile acids stimulate the expression of genes involved vate the farnesoid X receptor (FXR),the mechanism in bile acid transport,such as the intestinal bile acid–underlying bile acid–mediated repression of CYP7A1binding protein (I-BABP ),and repress CYP7A1and other remained unclear.We have used a potent,nonsteroi-genes encoding enzymes involved in bile acid biosyn-dal FXR ligand to show that FXR induces expression thesis,such as CYP8B1,which converts chenodeoxy-of small heterodimer partner 1(SHP-1),an atypical cholic acid (CDCA)to cholic acid,and CYP27,which member of the nuclear receptor family that lacks a catalyzes the first step in the alternative,“acidic”path-DNA-binding domain.SHP-1represses expression of way for bile acid synthesis (Russell and Setchell,1992;CYP7A1by inhibiting the activity of liver receptor ho-Javitt,1994;Russell,1999).Recently,FXR was shown molog 1(LRH-1),an orphan nuclear receptor that is to be a bile acid receptor (Wang et al.,1996;Makishima known to regulate CYP7A1expression positively.This et al.,1999;Parks et al.,1999).Several different bile bile acid–activated regulatory cascade provides a acids,including CDCA and its glycine and taurine conju-molecular basis for the coordinate suppression of gates,bind and activate FXR at physiologic concentra-CYP7A1and other genes involved in bile acid biosyn-tions.Moreover,FXR response elements (FXREs)were identified in both the mouse and human I-BABP promot-thesis.ers (Grober et al.,1999;Makishima et al.,1999),which provided strong evidence that FXR mediates the posi-Introduction

tive effects of bile acids on I-BABP expression.Notably,the rank order of bile acids that activate FXR correlates Cholesterol is essential for a number of cellular func-with that for repression of CYP7A1in a hepatocyte-tions,including membrane biogenesis and steroid hor-derived cell line (Makishima et al.,1999).These data mone and bile acid biosynthesis.However,in excess,suggested that FXR also has a role in the negative ef-cholesterol can contribute to disease processes such fects of bile acids on gene expression.However,since as atherosclerosis and gallstone formation.Therefore,the region of the CYP7A1promoter that is necessary cholesterol biosynthesis and catabolism must be coor-for bile acid–mediated repression lacks a strong FXR-dinately regulated.The metabolism of cholesterol to bile binding site (Chiang and Stroup,1994;Chiang et al.,acids represents a major pathway for its elimination 2000),it seemed unlikely that this repression was a di-from the body,accounting for approximately half of daily rect effect of FXR.Thus,the molecular mechanism for excretion.Cytochrome P4507A (CYP7A1)is a liver-spe-bile acid–mediated repression of CYP7A1remained cific enzyme that catalyzes the first and rate-limiting in question.

step in one of the two pathways for bile acid biosynthesis In this report,we have used a potent,nonsteroidal FXR (Chiang,1998;Russell and Setchell,1992).The gene ligand to demonstrate that FXR regulates the hepatic encoding CYP7A1is regulated by a variety of small,expression of small heterodimer partner 1(SHP-1;lipophilic molecules,including steroid and thyroid hor-NR0B2),an atypical,orphan member of the nuclear re-mones,cholesterol,and bile acids.Notably,CYP7A1ceptor family that lacks a DNA-binding domain (Seol et expression is stimulated by cholesterol feeding and re-al.,1996).SHP-1has been shown to bind to other nu-pressed by bile acids.Thus,CYP7A1is under both feed-clear receptors and to repress their transcriptional activ-forward and feedback regulation.

ities (Seol et al.,1996;M
asuda et al.,1997;Johansson CYP7A1expression is regulated by several members

ities (Seol et al.,1996;Masuda et al.,1997;Johansson CYP7A1expression is regulated by several members

et al.,1999;Lee et al.,2000).We show that SHP-1re-presses the CYP7A1promoter through interaction with liver receptor homolog 1(LRH-1;NR5A2),an orphan To whom correspondence should be addressed (e-mail:sak15922@

http://www.doczj.com/doc/b3f34e22011ca300a7c39009.html ).

nuclear receptor that binds as a monomer to a response

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