HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Winegar, D. A. Articles by Hawke, R. L. Search for Related Content PubMed PubMed Citation Articles by Winegar, D. A. Articles by Hawke, R. L. Social Bookmarking                      What's this?

Journal of Lipid Research, Vol 37, 179-191, Copyright © 1996 by Lipid Research, Inc.

ARTICLES

Effects of cyclosporin on cholesterol 27-hydroxylation and LDL receptor activity in HepG2 cells

DA Winegar, JA Salisbury, SS Sundseth and RL Hawke
Division of Pharmacokinetics and Drug Metabolism, Glaxo Wellcome Inc., Research Triangle Park, NC 27709, USA.

The hypothesis that mitochondrial sterol 27-hydroxylase plays a role in the sterol-mediated down-regulation of LDL receptor activity was evaluated in HepG2 cells. 27-Hydroxycholesterol was found to be more potent at suppressing LDL receptor activity than cholesterol (IC50 values of 8 mu M and 142 mu M for 27-hydroxycholesterol and cholesterol, respectively) when the sterols were delivered to cells from 2-hydroxypropyl-beta-cyclodextrin (beta-CD)-solubilized solutions. Cyclosporin, an immunosuppressant which has been shown to inhibit the 27-hydroxylation of sterols, was used to assess whether the formation of endogenous 27-hydroxycholesterol was required for the cholesterol- induced suppression of LDL receptor activity. Cyclosporin dose- dependently inhibited the 27-hydroxylation of cholesterol by HepG2 mitochondria (Ki = 0.25 mu M) and HepG2 cell cultures (IC50 = 1 mu M). At 1 mu M, cyclosporin had no effect on LDL receptor activity, and did not prevent the suppression of LDL receptor activity caused by: 1) the addition of beta-CD-solubilized cholesterol, 2) the receptor-mediated uptake of beta-VLDL, or 3) the inhibition of cholesterol esterification. In contrast, 10 mu M cyclosporin was found to inhibit the esterification of cholesterol and to increase the cellular level of free cholesterol resulting in suppression of LDL receptor activity. These results suggest that if mitochondrial sterol 27-hydroxylase plays a role in the regulation of LDL receptor activity, it is not through the formation of potent regulatory oxysterols, but through its effects on the availability and/or size of the free cholesterol pool regulating LDL receptor activity.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				D. Rodriguez-Agudo, S. Ren, P. B. Hylemon, K. Redford, R. Natarajan, A. Del Castillo, G. Gil, and W. M. Pandak Human StarD5, a cytosolic StAR-related lipid binding protein J. Lipid Res., August 1, 2005; 46(8): 1615 - 1623. [Abstract] [Full Text] [PDF]

				E. Hall, P. Hylemon, Z. Vlahcevic, D. Mallonee, K. Valerie, N. Avadhani, and W. Pandak Overexpression of CYP27 in hepatic and extrahepatic cells: role in the regulation of cholesterol homeostasis Am J Physiol Gastrointest Liver Physiol, July 1, 2001; 281(1): G293 - G301. [Abstract] [Full Text] [PDF]

				C. L. Baum Weight Gain and Cardiovascular Risk After Organ Transplantation JPEN J Parenter Enteral Nutr, May 1, 2001; 25(3): 114 - 119. [Abstract] [PDF]

				G. J. Schroepfer Jr. Oxysterols: Modulators of Cholesterol Metabolism and Other Processes Physiol Rev, January 1, 2000; 80(1): 361 - 554. [Abstract] [Full Text] [PDF]

				J. Wu, Y. H. Zhu, and S. B. Patel Cyclosporin-induced dyslipoproteinemia is associated with selective activation of SREBP-2 Am J Physiol Endocrinol Metab, December 1, 1999; 277(6): E1087 - E1094. [Abstract] [Full Text] [PDF]

				G. D. Luker, K. R. Nilsson, D. F. Covey, and D. Piwnica-Worms Multidrug Resistance (MDR1) P-glycoprotein Enhances Esterification of Plasma Membrane Cholesterol J. Biol. Chem., March 12, 1999; 274(11): 6979 - 6991. [Abstract] [Full Text] [PDF]