Biomaterial Database

7-Dehydrocholesterol down-regulates cholesterol biosynthesis in cultured Smith-Lemli-Opitz syndrome skin fibroblasts. 1998

M Honda, and G S Tint, and A Honda, and L B Nguyen, and T S Chen, and S Shefer

Department of Medicine, The Liver Center, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark 07103, USA.

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 microg/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 microg/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.

UI	MeSH Term	Description	Entries
D007654	Ketoconazole	Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients.	Nizoral,R-41400,R41,400,R41400,R 41400
D002478	Cells, Cultured	Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.	Cultured Cells,Cell, Cultured,Cultured Cell
D002784	Cholesterol	The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.	Epicholesterol
D003684	Dehydrocholesterols	Cholesterol derivatives having an additional double bond in any position. The prevalent isomer 7-dehydrocholesterol is a precursor of cholesterol and of vitamin D3.	(Z)-3 beta-Hydroxycholesta-5,27(20)-diene
D005347	Fibroblasts	Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules.	Fibroblast
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006903	Hydroxymethylglutaryl CoA Reductases	Enzymes that catalyze the reversible reduction of alpha-carboxyl group of 3-hydroxy-3-methylglutaryl-coenzyme A to yield MEVALONIC ACID.	HMG CoA Reductases,3-Hydroxy-3-methylglutaryl CoA Reductase,HMG CoA Reductase,Hydroxymethylglutaryl CoA Reductase,3 Hydroxy 3 methylglutaryl CoA Reductase,CoA Reductase, 3-Hydroxy-3-methylglutaryl,Reductase, 3-Hydroxy-3-methylglutaryl CoA
D019082	Smith-Lemli-Opitz Syndrome	An autosomal recessive disorder of CHOLESTEROL metabolism. It is caused by a deficiency of 7-dehydrocholesterol reductase, the enzyme that converts 7-dehydrocholesterol to cholesterol, leading to an abnormally low plasma cholesterol. This syndrome is characterized by multiple CONGENITAL ABNORMALITIES, growth deficiency, and INTELLECTUAL DISABILITY.	7-Dehydrocholesterol Reductase Deficiency,Hyperotosis Corticalis Generalisata Familiaris,Lethal Acrodysgenital Syndrome,Polydactyly, Sex Reversal, Renal Hypoplasia, And Unilobar Lung,RSH Syndrome,RSH-SLO Syndrome,Rutledge Friedman Harrod Syndrome,Rutledge Lethal Multiple Congenital Anomaly Syndrome,SLO Syndrome,Smith Lemli Opitz syndrome, type 1,Smith-Lemli-Opitz Syndrome, Type 1,Smith-Lemli-Opitz Syndrome, Type 2,Smith-Lemli-Opitz Syndrome, Type I,Smith-Lemli-Opitz Syndrome, Type II,7-Dehydrocholesterol Reductase Deficiencies,Acrodysgenital Syndrome, Lethal,Acrodysgenital Syndromes, Lethal,Deficiencies, 7-Dehydrocholesterol Reductase,Deficiency, 7-Dehydrocholesterol Reductase,Lethal Acrodysgenital Syndromes,RSH SLO Syndrome,RSH Syndromes,RSH-SLO Syndromes,Reductase Deficiencies, 7-Dehydrocholesterol,Reductase Deficiency, 7-Dehydrocholesterol,SLO Syndromes,Smith Lemli Opitz Syndrome,Smith Lemli Opitz Syndrome, Type 2,Smith Lemli Opitz Syndrome, Type I,Smith Lemli Opitz Syndrome, Type II,Syndrome, Lethal Acrodysgenital,Syndrome, RSH,Syndrome, SLO,Syndromes, RSH,Syndromes, SLO
D019161	Hydroxymethylglutaryl-CoA Reductase Inhibitors	Compounds that inhibit HYDROXYMETHYLGLUTARYL COA REDUCTASES. They have been shown to directly lower CHOLESTEROL synthesis.	HMG-CoA Reductase Inhibitor,HMG-CoA Reductase Inhibitors,Hydroxymethylglutaryl-CoA Reductase Inhibitor,Statin,Statins, HMG-CoA,Inhibitors, HMG-CoA Reductase,Inhibitors, Hydroxymethylglutaryl-CoA,Inhibitors, Hydroxymethylglutaryl-Coenzyme A,Statins,HMG CoA Reductase Inhibitor,HMG CoA Reductase Inhibitors,HMG-CoA Statins,Hydroxymethylglutaryl CoA Reductase Inhibitor,Hydroxymethylglutaryl CoA Reductase Inhibitors,Hydroxymethylglutaryl-CoA Inhibitors,Hydroxymethylglutaryl-Coenzyme A Inhibitors,Inhibitors, HMG CoA Reductase,Inhibitors, Hydroxymethylglutaryl CoA,Inhibitors, Hydroxymethylglutaryl Coenzyme A,Inhibitors, Hydroxymethylglutaryl-CoA Reductase,Reductase Inhibitor, Hydroxymethylglutaryl-CoA,Reductase Inhibitors, HMG-CoA,Reductase Inhibitors, Hydroxymethylglutaryl-CoA,Statins, HMG CoA