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) An erratum has been published All Versions of this Article: R800054-JLR200v1 50/Supplement/S15    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brown, M. S. Articles by Goldstein, J. L. Search for Related Content PubMed PubMed Citation Articles by Brown, M. S. Articles by Goldstein, J. L. Related Collections Related Webpages Social Bookmarking                      What's this?

Journal of Lipid Research, Vol. 50, S15-S27, April 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Special Feature

Cholesterol feedback: from Schoenheimer's bottle to Scap's MELADL

Michael S. Brown¹ and Joseph L. Goldstein¹

Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046

The original research described in this review was supported by grants from the National Institutes of Health (HL20948), the Perot Family Foundation, and the Moss Heart Foundation.

Published, JLR Papers in Press, October 29, 2008.

¹ To whom correspondence should be addressed. e-mail: mike.brown{at}utsouthwestern.edu (M.S.B); joe.goldstein{at}utsouthwestern.edu (J.L.G.)

ABSTRACT

Cholesterol biosynthesis is among the most intensely regulated processes in biology. Synthetic rates vary over hundreds of fold depending on the availability of an external source of cholesterol. Studies of this feedback regulatory process have a rich history. The field began 75 years ago when Rudolf Schoenheimer measured cholesterol balance in mice in a bottle. He found that cholesterol feeding led to decreased cholesterol synthesis, thereby introducing the general phenomenon by which end products of biosynthetic pathways inhibit their own synthesis. Recently, cholesterol feedback has been explained at a molecular level with the discovery of membrane-bound transcription factors called sterol regulatory element-binding proteins (SREBPs), and an appreciation of the sterol-sensing role of their partner, an escort protein called Scap. The key element in Scap is a hexapeptide sequence designated MELADL (rhymes with bottle). Thus, over 75 years, Schoenheimer's bottle led to Scap's MELADL. In addition to their basic importance in membrane biology, these studies have implications for the regulation of plasma cholesterol levels and consequently for the development of atherosclerotic plaques, myocardial infarctions, and strokes. In this article we review the major milestones in the cholesterol feedback story.

Supplementary key words cholesterol biosynthesis • LDL receptor • SREBP pathway • Insig • oxysterols • HMG-CoA reductase • CopII-coated vesicles • membrane proteins • historical aspects

Abbreviations: bHLH-Zip, basic-helix-loop-helix-leucine zipper; CHO, Chinese hamster ovary; ER, endoplasmic reticulum; FH, familial hypercholesterolemia; HMG-CoA, 3-hydroxy-3-methylglutaryl CoA; S1P, site-1 protease; S2P, site-2 protease; Scap, SREBP cleavage-activating protein; SRE, sterol regulatory element; SREBP, SRE-binding protein

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

Related Webpages: