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J. Biol. Chem., Vol. 276, Issue 32, 30118-30126, August 10, 2001
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From the Departments of Medicine, University of California, San
Francisco and the Metabolism Section, Department of Veterans Affairs
Medical Center, San Francisco, California 94121
The host response to infection is associated with
several alterations in lipid metabolism that promote lipoprotein
production. These changes can be reproduced by lipopolysaccharide (LPS)
administration. LPS stimulates hepatic cholesterol synthesis and
suppresses the conversion of cholesterol to bile acids. LPS
down-regulates hepatic cholesterol 7
In Vivo and in Vitro Regulation of Sterol
27-Hydroxylase in the Liver during the Acute Phase Response
POTENTIAL ROLE OF HEPATOCYTE NUCLEAR FACTOR-1*
,
-hydroxylase, the rate-limiting
enzyme in the classic pathway of bile acid synthesis. We now
demonstrate that LPS markedly decreases the activity of sterol
27-hydroxylase, the rate-limiting enzyme in the alternate pathway of
bile acid synthesis, in the liver of Syrian hamsters. Moreover, LPS
progressively decreases hepatic sterol 27-hydroxylase mRNA levels
by 75% compared with controls over a 24-h treatment period. LPS also
decreases oxysterol 7-hydroxylase mRNA levels in mouse liver.
In vitro studies in HepG2 cells demonstrate that tumor
necrosis factor and interleukin (IL)-1 decrease sterol
27-hydroxylase mRNA levels by 48 and 80%, respectively, whereas
IL-6 has no such effect. The IL-1-induced decrease in sterol
27-hydroxylase mRNA expression occurs early, is sustained for
48 h, and requires very low doses. In vivo IL-1 treatment also lowers hepatic sterol 27-hydroxylase mRNA levels in
Syrian hamsters. Studies investigating the molecular mechanisms of
LPS-induced decrease in sterol 27-hydroxylase show that LPS markedly
decreases mRNA and protein levels of hepatocyte nuclear factor-1
(HNF-1), a transcription factor that regulates sterol 27-hydroxylase,
in the liver. Moreover, LPS decreases the binding activity of HNF-1 by
70% in nuclear extracts in hamster liver, suggesting that LPS may
down-regulate sterol 27-hydroxylase by decreasing the binding of HNF-1
to its promoter. Coupled with our earlier studies on cholesterol
7-hydroxylase, these data indicate that LPS suppresses both the
classic and alternate pathways of bile acid synthesis. A decrease in
bile acid synthesis in liver would reduce cholesterol catabolism and
thereby contribute to the increase in hepatic lipoprotein production
that is induced by LPS and cytokines.
*
This work was supported by grants from the Research Service
of the Department of Veterans Affairs.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.
To whom correspondence should be addressed: Metabolism Section
(111F), Dept. of Veterans Affairs Medical Center, 4150 Clement St., San
Francisco, CA 94121. Tel: 415-750-2005; Fax: 415-750-6927; E-mail: rmemon@itsa.ucsf.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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