TREATMENT OF THE CHOLESTEROL BIOSYNTHETIC DEFECT IN SMITH-LEMLI-OPITZSYNDROME REPRODUCED IN RATS BY BM 15.766

Background & Aims: The Smith-Lemli-Opitz syndrome is a recessive inher ited disorder characterized by neurological developmental defects and dysmorphic features with a defect in cholesterol synthesis at the conv ersion of 7-dehydrocholesterol to cholesterol. BM 15.766 inhibits 7-de hydrocholesterol-Delta(7)-reductase and reproduces the biochemical def ect. The aim of this study was to investigate the effects of cholester ol, cholic acid, and lovastatin feeding on rats fed BM 15.766. Methods : Plasma cholesterol and 7-dehydrocholesterol concentrations were rela ted to the hepatic 3-hydroxy-3-methylglutauyl-coenzyme A (HMG-CoA) red uctase. Results: With the inhibitor treatment, plasma cholesterol conc entrations decreased 67%; 7-dehydrocholesterol concentrations increase d from trace to 17 mg/dL; and hepatic HMG-CoA reductase activity and m essenger RNA levels were stimulated 74% and two times, respectively. I n inhibitor-treated rats, feeding cholesterol increased plasma cholest erol concentrations 3.7 times, decreased 7-dehydrocholesterol concentr ations 88%, and reduced elevated HMG-CoA reductase activity and messen ger RNA levels 74% and 49%. Feeding cholic acid increased plasma chole sterol without reducing 7-dehydrocholesterol concentrations. The combi nation of cholic acid and cholesterol enhanced plasma cholesterol 9.5 times without decreasing 7-dehydrocholesterol levels. Feeding lovastat in depressed plasma cholesterol further without reducing 7-dehydrochol esterol levels. Conclusions: Cholesterol is essential to correct abnor mal cholesterol synthesis induced by BM 15.766 in rats by expanding th e pool and inhibiting HMG-CoA reductase. Neither cholic acid nor lovas tatin are effective separately, but cholic acid plus cholesterol may o ffer some additional benefit.