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

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Honda, M. Articles by Shefer, S. Search for Related Content PubMed PubMed Citation Articles by Honda, M. Articles by Shefer, S. Social Bookmarking                      What's this?

The Journal of Lipid Research, Vol. 39, 647-657, March 1998
Copyright © 1998 by Lipid Research, Inc.

Original Article

7-Dehydrocholesterol down-regulates cholesterol biosynthesis in cultured Smith-Lemli-Opitz syndrome skin fibroblasts

Correspondence to: G. S. Tint.

The Smith-Lemli-Opitz syndrome (SLOS) is a common birth defect–mental retardation syndrome caused by a defect in the enzyme that reduces 7-dehydrocholesterol to cholesterol. Because of this block, patients' plasma cholesterol levels are generally low while 7-dehydrocholesterol concentrations are markedly elevated. In addition, plasma total sterols are abnormally low and correlate negatively with the percent of 7-dehydrocholesterol (r = -0.65, P < 0.0001) suggesting that 7-dehydrocholesterol might inhibit the activity of HMG-CoA reductase. Cultured skin fibroblasts from SLOS patients grown in fetal bovine serum or for 1 day in delipidated medium contain little 7-dehydrocholesterol (3 ± 1% of total sterols) and HMG-CoA reductase activities are indistinguishable from that measured in control cells. However, raising the 7-dehydrocholesterol concentration to 20 ± 3% of total sterols, equal to the mean proportion in plasma of SLOS patients, by either growing cells for 1 week in delipidated medium or adding 20 µg/ml 7-dehydrocholesterol directly to the cells reduced HMG-CoA reductase activities from 74 ± 7 to 9 ± 2 pmol/min per mg protein, or from 92 ± 22 to 16 ± 4 pmol/min per mg protein, respectively (P < 0.01). In contrast, adding 20 µg/ml cholesterol evoked a 2- to 4-fold lesser suppression of activity (39 ± 8 pmol/min per mg protein, P < 0.05, vs. 7-dehydrocholesterol). HMG-CoA synthase and LDL binding were inhibited equally by 7-dehydrocholesterol and cholesterol. Ketaconazole prevented the down-regulation of HMG-CoA reductase by 7-dehydrocholesterol, suggesting that an hydroxylated derivative of 7-dehydrocholesterol may be especially important in suppressing cholesterol synthesis.

These results demonstrate that 7-dehydrocholesterol, perhaps as an hydroxylated derivative(s), is a very effective feedback inhibitor of HMG-CoA reductase.—Honda, M., G. S. Tint, A. Honda, L. B. Nguyen, T. S. Chen, and S. Shefer. 7-Dehydrocholesterol down-regulates cholesterol biosynthesis in cultured Smith-Lemli-Opitz syndrome skin fibroblasts. J. Lipid Res. 1998. 39: 647–657.

Supplementary key words: HMG-CoA reductase, HMG-CoA synthase, ketoconazole, LDL receptor, plasma sterols

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				D. Cunningham, D. Swartzlander, S. Liyanarachchi, R. V. Davuluri, and G. E. Herman Changes in gene expression associated with loss of function of the NSDHL sterol dehydrogenase in mouse embryonic fibroblasts J. Lipid Res., June 1, 2005; 46(6): 1150 - 1162. [Abstract] [Full Text] [PDF]

				C. Fernandez, M. Martin, D. Gomez-Coronado, and M. A. Lasuncion Effects of distal cholesterol biosynthesis inhibitors on cell proliferation and cell cycle progression J. Lipid Res., May 1, 2005; 46(5): 920 - 929. [Abstract] [Full Text] [PDF]

				G. E. Herman Disorders of cholesterol biosynthesis: prototypic metabolic malformation syndromes Hum. Mol. Genet., April 2, 2003; 12(90001): R75 - 88. [Abstract] [Full Text] [PDF]

				H.-J. Gober, M. Kistowska, L. Angman, P. Jeno, L. Mori, and G. De Libero Human T Cell Receptor {gamma}{delta} Cells Recognize Endogenous Mevalonate Metabolites in Tumor Cells J. Exp. Med., January 20, 2003; 197(2): 163 - 168. [Abstract] [Full Text] [PDF]

				A. S. Pappu, R. D. Steiner, S. L. Connor, D. P. Flavell, D. S. Lin, L. Hatcher, D. R. Illingworth, and W. E. Connor Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretion J. Lipid Res., October 1, 2002; 43(10): 1661 - 1669. [Abstract] [Full Text] [PDF]

				B. Ruan, J. Tsai, W. K. Wilson, and G. J. Schroepfer , Jr. Aberrant pathways in the late stages of cholesterol biosynthesis in the rat: origin and metabolic fate of unsaturated sterols relevant to the Smith-Lemli-Opitz syndrome J. Lipid Res., November 1, 2000; 41(11): 1772 - 1782. [Abstract] [Full Text]

				R. D. Steiner, L. M. Linck, D. P. Flavell, D. S. Lin, and W. E. Connor Sterol balance in the Smith-Lemli-Opitz syndrome: reduction in whole body cholesterol synthesis and normal bile acid production J. Lipid Res., September 1, 2000; 41(9): 1437 - 1447. [Abstract] [Full Text]

				J.-C. Jang, S. Fujioka, M. Tasaka, H. Seto, S. Takatsuto, A. Ishii, M. Aida, S. Yoshida, and J. Sheen A critical role of sterols in embryonic patterning and meristem programming revealed by the fackel mutants of Arabidopsis thaliana Genes & Dev., June 15, 2000; 14(12): 1485 - 1497. [Abstract] [Full Text]

				C. Roux, C. Wolf, N. Mulliez, W. Gaoua, V. Cormier, F. Chevy, and D. Citadelle Role of cholesterol in embryonic development Am. J. Clinical Nutrition, May 1, 2000; 71(5): 1270S - 1279. [Abstract] [Full Text] [PDF]

				W. Gaoua, C. Wolf, F. Chevy, F. Ilien, and C. Roux Cholesterol deficit but not accumulation of aberrant sterols is the major cause of the teratogenic activity in the Smith-Lemli-Opitz syndrome animal model J. Lipid Res., April 1, 2000; 41(4): 637 - 646. [Abstract] [Full Text]

				J. G. Morris Ineffective Vitamin D Synthesis in Cats Is Reversed by an Inhibitor of 7-Dehydrocholestrol-{Delta}7-Reductase J. Nutr., April 1, 1999; 129(4): 903 - 908. [Abstract] [Full Text]

				W. Gaoua, F. Chevy, C. Roux, and C. Wolf Oxidized derivatives of 7-dehydrocholesterol induce growth retardation in cultured rat embryos: a model for antenatal growth retardation in the Smith-Lemli-Opitz syndrome J. Lipid Res., March 1, 1999; 40(3): 456 - 463. [Abstract] [Full Text]