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Abnormal cholesterol biosynthesis in sitosterolaemia and the Smith‐Lemli‐Opitz syndrome
Author(s) -
Salen G.,
Shefer S.,
Batta A. K.,
Tint G. S.,
Xu G.,
Honda A.
Publication year - 1996
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/bf01799100
Subject(s) - smith–lemli–opitz syndrome , sterol , cholesterol , reductase , biosynthesis , medicine , endocrinology , lathosterol , campesterol , enzyme , biology , 7 dehydrocholesterol reductase , cholesterol synthesis , hmg coa reductase , biochemistry
Summary We investigated the enzyme defects in two inherited disorders of cholesterol biosynthesis: sitosterolaemia and the Smith‐Lemli‐Opitz syndrome. In sitosterolaemic homozygotes, plasma plant sterols (sitosterol and campesterol) concentrations are elevated because of enhanced intestinal absorption and diminished removal. Underlying these changes is very low cholesterol biosynthesis to provide extra sterol for cell growth. Extremely reduced activities of HMG‐CoA reductase, the rate‐controlling enzyme for cholesterol biosynthesis, caused by deficient HMG‐CoA reductase mRNA is responsible and is the suspected inherited abnormality. The Smith‐Lemli‐Opitz syndrome is caused by a block in the last reaction in the cholesterol biosynthetic pathway, the conversion of 7‐dehydrocholesterol to cholesterol, which is catalysed by 7‐dehydrocholesterol Δ 7 ‐reductase. As a result, low plasma and tissue cholesterol with high 7‐dehydrocholesterol levels are found in homozygotes, who show characteristic phenotypes of mental retardation, facial dysmorphism, and organ and limb congenital anomalies. Similar biochemical findings are produced in rats fed BM 15,766, an inhibitor of 7‐dehydrocholesterol Δ 7 ‐reductase. Interestingly, feeding cholesterol can suppress abnormal cholesterol biosynthesis and improve symptoms in homozygotes and rats fed BM 15,766.