Regulation of cholesterol biosynthetic pathway in patients with the Smith-Lemli-Opitz syndrome

The Smith-Lemli-Opitz syndrome (SLOS) is a recessively inherited birth diso rder caused by a defect in 7-dehydrocholesterol (3 beta-hydroxysteroid) Del ta(7)-reductase, the final enzyme in cholesterol biosynthesis. To investiga te in vivo regulation of the cholesterol biosynthetic pathway in SLOS, we m easured hepatic microsomal sterol concentrations and activities of several key enzymes in the pathway, including HMG-CoA synthase, HMG-CoA reductase, squalene synthase and 7-dehydrocholesterol Delta(7)-reductase in liver spec imens from a patient with SLOS and 11 controls. Hepatic microsomal 7-dehydr ocholesterol Delta(7)-reductase activity in the patient was less than 1% of the control mean, and decreased cholesterol concentration and markedly inc reased 7- and 8-dehydrocholesterol concentrations were observed in the pati ent's microsomes. HMG-CoA synthase and squalene synthase activities in the patient were upregulated to 149% and 532%, respectively, while the activity of HMG-CoA reductase, the rate-limiting enzyme in the pathway, was reduced to 39% of the control mean. Downregulation of HMG-CoA reductase activity i n SLOS was supported by measuring plasma levels of mevalonic acid, the imme diate product of HMG-CoA reductase. The levels in SLOS patients (n=9) were significantly low compared with age-matched controls (n=8) (12 +/- 2 vs 28 +/- 6 nmol/L, p < 0.05). These results suggest that in most SLOS patients i n vivo HMG-CoA reductase is not stimulated in spite of blocked cholesterol biosynthetic pathway and reduced plasma and hepatic cholesterol concentrati ons.