7-DEHYDROCHOLESTEROL DOWN-REGULATES CHOLESTEROL-BIOSYNTHESIS IN CULTURED SMITH-LEMLI-OPITZ-SYNDROME SKIN FIBROBLASTS

The Smith-Lemli-Opitz syndrome (SLOS) is a common birth defect-mental retardation syndrome caused by a defect in the enzyme that reduces 7-d ehydrocholesterol to cholesterol. Because of this block, patients' pla sma cholesterol levels are generally low while 7-dehydrocholesterol co ncentrations are markedly elevated. In addition, plasma total sterols are abnormally low and correlate negatively with the percent of 7-dehy drocholesterol (r = -0.65, P < 0.0001) suggesting that 7-dehydrocholes terol might inhibit the activity of HMG-CoA reductase. Cultured skin f ibroblasts from SLOS patients grown in fetal bovine serum or for 1 day in delipidated medium contain little 7-dehydrocholesterol (3 +/- 1% o f total sterols) and HMG-CoA reductase activities are indistinguishabl e from that measured in control cells. However, raising the 7-dehydroc holesterol concentration to 20 +/- 3% of total sterols, equal to the m ean proportion in plasma of SLOS patients, by either growing cells for 1 week in delipidated medium or adding 20 mu g/ml 7-dehydrocholestero l directly to the cells reduced HMG-CoA reductase activities from 74 /- 7 to 9 +/- 2 pmol/min per mg protein, or from 92 +/- 21 to 16 +/- 4 pmol/min per mg protein, respectively P < 0.01). In contrast, adding 20 mu g/ml cholesterol evoked a 2- to 4-fold lesser suppression of act ivity (39 +/- 8 pmol/min per mg protein, P < 0.05, vs. 7-dehydrocholes terol). HMG-CoA synthase ald LDL binding ere inhibited equally by 7-de hydrocholesterol and cholesterol. Ketaconazole prevented the down-regu lation of HMG-CoA reductase by 7-dehydrocholesterol, suggesting that a n hydroxylated derivative of 7-dehydrocholesterol may be especially im portant in suppressing cholesterol synthesis. These results demonstrat e that 7-dehydrocholesterol, perhaps as an hydroxylated derivative(s), is a very effective feedback inhibitor of HMG-CoA reductase.