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Journal of Lipid Research, Vol. 41, 1772-1782, November 2000
Copyright © 2000 by Lipid Research, Inc.

Original Article

Aberrant pathways in the late stages of cholesterol biosynthesis in the rat: origin and metabolic fate of unsaturated sterols relevant to the Smith-Lemli-Opitz syndrome

Correspondence to: William K. Wilson

Minor aberrant pathways of cholesterol biosynthesis normally produce only trace levels of abnormal sterol metabolites but may assume major importance when an essential biosynthetic step is blocked. Cholesta-5,8-dien-3ß-ol, its ^5,7 isomer, and other noncholesterol sterols accumulate in subjects with the Smith-Lemli-Opitz syndrome (SLOS), a severe developmental disorder caused by a defective ⁷ sterol reductase gene. We have explored the formation and metabolism of unsaturated sterols relevant to SLOS by incubating tritium-labeled ^5,8, ^6,8, ^6,8(14), ^5,8(14), and ⁸ sterols with rat liver preparations. More than 60 different incubations were carried out with washed microsomes or the 10,000 g supernatant under aerobic or anaerobic conditions; some experiments included addition of cofactors, fenpropimorph (a ⁸;–⁷ isomerase inhibitor), and/or AY-9944 (a ⁷ reductase inhibitor). The tritium-labeled metabolites from each incubation were identified by silver ion high performance liquid chromatography on the basis of their coelution with unlabeled authentic standards, as free sterols and/or acetate derivatives. The ^5,8 sterol was converted slowly to cholesterol via the ^5,7 sterol, which also slowly isomerized back to the ^5,8 sterol. The ^6,8 sterol was metabolized rapidly to cholesterol by an oxygen-requiring pathway via the ^7,9(11), ⁸, ⁷, and ^5,7 sterols as well as by an oxygen-independent route involving initial isomerization to the ^5,7 sterol. The ⁸ sterol was partially metabolized to ^5,8, ^6,8, ^7,9(11), and ^5,7,9(11) sterols when isomerization to ⁷ was blocked.

The combined results were used to formulate a scheme of normal and aberrant biosynthetic pathways that illuminate the origin and metabolic fate of abnormal sterols observed in SLOS and chondrodysplasia punctata. — Ruan, B., J. Tsai, W. K. Wilson, and G. J. Schroepfer, Jr. Aberrant pathways in the late stages of cholesterol biosynthesis in the rat: origin and metabolic fate of unsaturated sterols relevant to the Smith-Lemli-Opitz syndrome. J. Lipid Res. 2000. 41: 1772;–1782.

Supplementary key words: cholesta-5,8-dien-3ß-ol, Ag⁺-HPLC, microsomes, tritium-labeled substrates, ⁸;–⁷ sterol isomerase, ⁵ desaturase, ⁷ reductase, SLOS

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