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J. Biol. Chem., Vol. 276, Issue 33, 30708-30716, August 17, 2001
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From the Dipartimento di Scienze Farmacologiche, Facoltà di
Farmacia, Università degli Studi di Milano, Milano 20133, Italy
Bile acids regulate the cholesterol
7
The Negative Effects of Bile Acids and Tumor Necrosis
Factor-
on the Transcription of Cholesterol 7-Hydroxylase
Gene (CYP7A1) Converge to Hepatic Nuclear Factor-4
A NOVEL MECHANISM OF FEEDBACK REGULATION OF BILE ACID SYNTHESIS
MEDIATED BY NUCLEAR RECEPTORS*
,
-hydroxylase gene (CYP7A1), which encodes the
rate-limiting enzyme in the classical pathway of bile acid synthesis.
Here we report a novel mechanism whereby bile acid feedback regulates
CYP7A1 transcription through the nuclear receptor
hepatocyte nuclear factor-4 (HNF-4), which binds to the
bile acid response element (BARE) at nt 
149/118 relative to the
transcription start site. Using transient transfection assays of HepG2
cells with Gal4-HNF-4 fusion proteins, we show that chenodeoxycholic
acid (CDCA) dampened the transactivation potential of HNF-4.
Overexpression of a constitutive active form of MEKK1, an upstream
mitogen-activated protein kinase (MAPK) module triggered by stress
signals, strongly repressed the promoter activity of
CYP7A1 via the consensus sequence for HNF-4 embedded in the
BARE. Similarly, MEKK1 inhibited the activity of HNF-4 in the
Gal4-based assay. The involvement of the
MEKK1-dependent pathway in the bile acid-mediated
repression of CYP7A1 was confirmed by co-transfecting a
dominant negative form of the stress-activated protein kinase kinase,
SEK, which abolished the effect of CDCA upon CYP7A1
transcription. Treatment of transfected HepG2 cells with tumor necrosis
factor (TNF-), an activator of the MEKK1 pathway, led to the
repression of CYP7A1 via the HNF-4 site in the BARE.
TNF- also inhibited the transactivation potential of HNF-4.
Collectively, our results demonstrate for the first time that HNF-4, in
combination with a MAPK signaling pathway, acts as a bile acid sensor
in the liver. Furthermore, the effects of CDCA and TNF- converge to
HNF-4, which binds to the BARE of CYP7A1, suggesting a link
between the cascades elicited by bile acids and pro-inflammatory
stimuli in the liver.
*
This research was supported in part by a grant from the
Ministero dell'Università e della Ricerca Scientifica e
Tecnologica.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.
A recipient of a postdoctoral fellowship from the Italian Foreign
Ministry and a visiting fellow from the Departamento de Bioquìmica y Ciencias Biologicas, Universidad Nacional de San Luis, San Luis, Argentina.
§
To whom correspondence should be addressed: Dipartimento di Scienze
Farmacologiche, Facoltà di Farmacia, Università degli Studi
di Milano, via Balzaretti 9, Milano 20133, Italy. Tel.: 39-02-5835-8393; Fax: 39-02-5835-8391; E-mail:
Maurizio.Crestani@unimi.it.
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