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-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.