SMITH-LEMLI-OPITZ SYNDROME PRODUCED IN RATS WITH AY-9944 TREATED BY INTRAVENOUS-INJECTION OF LIPOPROTEIN CHOLESTEROL

A limitation to treating Smith-Lemli-Opitz infants by giving dietary c holesterol is their impaired ability to absorb cholesterol due to a de ficiency of bile acids. Since intravenously administered lipoprotein c holesterol should not require bile acids for uptake into tissues, we t ested the effects of this form of cholesterol on tissue cholesterol an d 7-dehydrocholesterol levels in an animal model. of SLO, created by f eeding rats 0.02% AY 9944. Intravenous administration of 15 mg of bovi ne cholesterol supertrate twice daily increased serum cholesterol leve ls from 11 to over 250 mg/dl. This treatment increased liver cholester ol levels from 309 to over 900 mu g/g and lowered hepatic 7-dehydrocho lesterol levels from 1546 to 909 mu g/g. A combination of iv cholester ol and 2% dietary cholesterol was most effective as it raised hepatic cholesterol levels to 1950 mu g/g, which is 50% above normal. 7-Dehydr ocholesterol levels were decreased to 760 mu g/g. Similar responses we re seen for heart, lung, kidney, and testes. Brain sterol levels were not significantly affected. AY 9944 caused a modest increase in hepati c HMG-CoA reductase activity. Administration of dietary cholesterol to gether with iv cholesterol lowered hepatic HMG-CoA reductase activity to barely detectable levels. The data indicate that the combination of iv and dietary cholesterol was most effective in raising cholesterol levels, lowering 7-dehydrocholesterol levels, and inhibiting de novo c holesterol biosynthesis. (C) 1997 Wiley-Liss, Inc.