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Originally published In Press as doi:10.1074/jbc.M205244200 on October 3, 2002

J. Biol. Chem., Vol. 277, Issue 50, 48158-48164, December 13, 2002
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Transport of Cholesterol into Mitochondria Is Rate-limiting for Bile Acid Synthesis via the Alternative Pathway in Primary Rat Hepatocytes*

William M. PandakDagger §, Shunlin RenDagger , Dalila MarquesDagger , Elizabeth HallDagger , Kaye RedfordDagger , Darrell Mallonee, Patricia Bohdan, Douglas HeumanDagger , Gregorio Gil||, and Phillip Hylemon

From the Departments of Dagger  Medicine,  Microbiology and Immunology, and || Biochemistry, Veterans Affairs Medical Center, and Virginia Commonwealth University, Richmond, Virginia 23298-0711

Bile acid synthesis occurs mainly via two pathways: the "classic" pathway, initiated by microsomal cholesterol 7alpha -hydroxylase (CYP7A1), and an "alternative" (acidic) pathway, initiated by sterol 27-hydroxylase (CYP27). CYP27 is located in the inner mitochondrial membrane, where cholesterol content is very low. We hypothesized that cholesterol transport into mitochondria may be rate-limiting for bile acid synthesis via the "alternative" pathway. Overexpression of the gene encoding steroidogenic acute regulatory (StAR) protein, a known mitochondrial cholesterol transport protein, led to a 5-fold increase in bile acid synthesis. An increase in StAR protein coincided with an increase in bile acid synthesis. CYP27 overexpression increased bile acid synthesis by <2-fold. The rates of bile acid synthesis following a combination of StAR plus CYP27 overexpression were similar to those obtained with StAR alone. TLC analysis of 14C-labeled bile acids synthesized in cells overexpressing StAR showed a 5-fold increase in muricholic acid; in chloroform-extractable products, a dramatic increase was seen in bile acid biosynthesis intermediates (27- and 7,27-hydroxycholesterol). High-performance liquid chromatography analysis showed that 27-hydroxycholesterol accumulated in the mitochondria of StAR-overexpressing cells only. These findings suggest that cholesterol delivery to the inner mitochondrial membrane is the predominant rate-determining step for bile acid synthesis via the alternative pathway.

* This work was supported by a grant from the Veterans Affairs Medical Center and National Institutes of Health Grant PO1 DK38030.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: Virginia Commonwealth University, Medical College of Virginia Campus, P. O. Box 980711, Richmond, VA 23298-0711. Tel.: 804-828-3849; Fax: 804-828-7430; E-mail: wmpandak@hsc.vcu.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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