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

The Smith-Lemli-Opitz syndrome (SLOS) is a com- mon birth defect-mental retardation syndrome caused by a defect in the enzyme that reduces 7-dehydrocholesterol to cholesterol. Because of this block, patients' plasma choles- terol levels are generally low while 7-dehydrocholesterol con- centrations are markedly elevated. In addition, plasma total sterols are abnormally low and correlate negatively with the percent of 7-dehydrocholesterol (r 5 2 0.65, P , 0.0001) sug- gesting that 7-dehydrocholesterol might inhibit the activity of HMG-CoA reductase. Cultured skin fibroblasts from SLOS pa- tients grown in fetal bovine serum or for 1 day in delipidated medium contain little 7-dehydrocholesterol (3 6 1% of total sterols) and HMG-CoA reductase activities are indistinguish- able from that measured in control cells. However, raising the 7-dehydrocholesterol concentration to 20 6 3% of total ste- rols, equal to the mean proportion in plasma of SLOS pa- tients, by either growing cells for 1 week in delipidated me- dium or adding 20 m g/ml 7-dehydrocholesterol directly to the cells reduced HMG-CoA reductase activities from 74 6 7 to 9 6 2 pmol/min per mg protein, or from 92 6 22 to 16 6 4 pmol/min per mg protein, respectively ( P , 0.01). In con- trast, adding 20 m g/ml cholesterol evoked a 2- to 4-fold lesser suppression of activity (39 6 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 es- pecially 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-Dehydro- cholesterol down-regulates cholesterol biosynthesis in cul- tured Smith-Lemli-Opitz syndrome skin fibroblasts. J. Lipid Res. 1998. 39: 647-657.