出版社：American Society for Biochemistry and Molecular Biology
摘要：Smith-Lemli-Opitz syndrome (SLOS) is an inherited autosomalrecessive cholesterol deficiency disorder. Our studies haveshown that in SLOS children, urinary mevalonate excretion isnormal and reflects hepatic HMG-CoA reductase activity but notultimate sterol synthesis. Hence, we hypothesized that in SLOSthere may be increased diversion of mevalonate to nonsterolisoprenoid synthesis. To test our hypothesis, we measured urinarydolichol and ubiquinone, two nonsterol isoprenoids, in 16 childrenwith SLOS and 15 controls, all fed a low-cholesterol diet. Theurinary excretion of both dolichol (P < 0.002) and ubiquinone(P < 0.02) in SLOS children was 7-fold higher than in controlchildren, whereas mevalonate excretion was comparable. In asubset of 12 SLOS children, a high-cholesterol diet decreasedurinary mevalonate excretion by 61% (P < 0.001), dolicholby 70% (P < 0.001), and ubiquinone by 67% (P < 0.03).Our hypothesis that in SLOS children, normal urinary mevalonateexcretion results from increased diversion of mevalonate intothe production of nonsterol isoprenoids is supported. Dietarycholesterol supplementation reduced urinary mevalonate and nonsterolisoprenoid excretion but did not change the relative ratiosof their excretion. Therefore, in SLOS, a secondary peripheralregulation of isoprenoid synthesis may be stimulated.Supplementary key words mevalonate • 24 hour urine • farnesyl pyrophosphate • sterols • 7-dehydrocholesterol
Abbreviations: 7-DHC, 7-dehydrocholesterol; 8-DHC, 8-dehydrocholesterol; GCRC, General Clinical Research Center; SLOS, Smith-Lemli-Opitz syndrome
