title: 7-Dehydrocholesterol down-regulates cholesterol biosynthesis in cultured Smith-Lemli-Opitz syndrome skin fibroblasts.
abstract: 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.
authors.affiliation: Department of Medicine, The Liver Center, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark 07103, USA.
authors.forename: M
authors.initials: M
authors.lastname: Honda
authors.forename: G S
authors.initials: GS
authors.lastname: Tint
authors.forename: A
authors.initials: A
authors.lastname: Honda
authors.forename: L B
authors.initials: LB
authors.lastname: Nguyen
authors.forename: T S
authors.initials: TS
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Shefer
mesh_terms: D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood; D003684:Dehydrocholesterols / Q000097:blood / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology; D019082:Smith-Lemli-Opitz Syndrome / Q000097:blood / Q000378:metabolism*
chemical_list: D003684:Dehydrocholesterols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; C016705:7-dehydrocholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D007654:Ketoconazole