J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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A more recent version of this article appeared on November 1, 2004

Papers In Press, published online ahead of print September 1, 2004
J. Lipid Res., doi:10.1194/jlr.M400233-JLR200
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Submitted on June 16, 2004
Revised on August 11, 2004
Accepted on August 23, 2004

Effect of increasing the expression of intracellular cholesterol transporters (StAR, MLN64, and SCP-2) on bile acid synthesis

Shunlin Ren, Phillip B. Hylemon, Dalila Marques, Elizabeth A. Hall, Kaye Redford, Gregorio Gil, and William M. Pandak

Department of Internal Medicine and Gastroenterology, Virginia Commonwealth University, Richmond, VA 23298-0341

Corresponding Author: mggray{at}vcu.edu

There are two major pathways of bile acid synthesis: the “neutral” pathway, initiated by highly regulated microsomal cholesterol 7alpha -hydroxylase, and an “alternative” pathway, initiated by mitochondrial sterol 27-hydroxylase (CYP27A1). In hepatocyte cultures, overexpression of CYP7A1 increases bile acid synthesis > 8-fold. However, overexpression of CYP27A1 in hepatocytes only increases bile acid synthesis by 1.5 fold, suggesting additional rate-limiting steps must be involved in the regulation of this pathway. The effects of increased expression of intracellular cholesterol transport proteins on bile acid synthesis have been investigated in the current study. Under culture conditions in which the “neutral”pathway was inactive, selective overexpression of the gene encoding steroidogenic acute regulatory protein (StAR), MLN64 (StAR homologue protein), and sterol carrier protein-2 (SCP-2) led to a 5.7-, 1.2-, and 1.7-fold increase, respectively, in the rates of bile acid synthesis in primary rat hepatocytes. Under culture conditions in which the “neutral”pathway was active and basal rates of bile acid synthesis are found to be 2-fold higher, both StAR (2-fold) and SCP-2 (1.3-fold) overexpression led to an increase in bile acid synthesis. However, MLN64 overexpression led to a 20% decrease in bile acid synthesis. Surprisingly, co-overexpression of MLN64 with StAR, SCP-2, or CYP7A1 blunted the upregulated bile acid synthesis by 48%, 47% and 45%, respectively. These results suggest that MLN64, in its full-length form, is not responsible for the transport cholesterol to the mitochondria or to the endoplasmic reticulum where CYP27A1 and CYP7A1 are located, respectively, that the intracellular trafficking of cholesterol is a complex process, and that each cholesterol-binding protein contributes in its own way to intracellular cholesterol movement.


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