HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: M600295-JLR200v1 47/12/2789    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pappu, A. S. Articles by Steiner, R. D. Search for Related Content PubMed PubMed Citation Articles by Pappu, A. S. Articles by Steiner, R. D. Social Bookmarking                      What's this?

Journal of Lipid Research, Vol. 47, 2789-2798, December 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Patient-Oriented Research

Increased nonsterol isoprenoids, dolichol and ubiquinone, in the Smith-Lemli-Opitz syndrome: effects of dietary cholesterol

Anuradha S. Pappu^1,*, William E. Connor^*, Louise S. Merkens, Julia M. Jordan^*, Jennifer A. Penfield, D. Roger Illingworth^* and Robert D. Steiner

^* Division of Endocrinology, Diabetes, and Clinical Nutrition, Department of Medicine, Oregon Health and Science University, Portland, OR 97239
Division of Endocrinology, Diabetes, and Clinical Nutrition, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239
Division of Endocrinology, Diabetes, and Clinical Nutrition, Departments of Pediatrics and Molecular and Medical Genetics, Child Development and Rehabilitation Center, Doernbecher Children's Hospital, Oregon Health and Science University, Portland, OR 97239

Published, JLR Papers in Press, September 18, 2006.

¹ To whom correspondence should be addressed. e-mail: pappua{at}ohsu.edu

ABSTRACT

Smith-Lemli-Opitz syndrome (SLOS) is an inherited autosomal recessive cholesterol deficiency disorder. Our studies have shown that in SLOS children, urinary mevalonate excretion is normal and reflects hepatic HMG-CoA reductase activity but not ultimate sterol synthesis. Hence, we hypothesized that in SLOS there may be increased diversion of mevalonate to nonsterol isoprenoid synthesis. To test our hypothesis, we measured urinary dolichol and ubiquinone, two nonsterol isoprenoids, in 16 children with SLOS and 15 controls, all fed a low-cholesterol diet. The urinary excretion of both dolichol (P < 0.002) and ubiquinone (P < 0.02) in SLOS children was 7-fold higher than in control children, whereas mevalonate excretion was comparable. In a subset of 12 SLOS children, a high-cholesterol diet decreased urinary mevalonate excretion by 61% (P < 0.001), dolichol by 70% (P < 0.001), and ubiquinone by 67% (P < 0.03). Our hypothesis that in SLOS children, normal urinary mevalonate excretion results from increased diversion of mevalonate into the production of nonsterol isoprenoids is supported. Dietary cholesterol supplementation reduced urinary mevalonate and nonsterol isoprenoid excretion but did not change the relative ratios of their excretion. Therefore, in SLOS, a secondary peripheral regulation 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

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?