J. Lipid Res.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Originally published In Press as doi:10.1194/jlr.M300409-JLR200 on November 16, 2003

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
M300409-JLR200v1
45/2/223    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zhang, J.
Right arrow Articles by Ory, D. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhang, J.
Right arrow Articles by Ory, D. S.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Journal of Lipid Research, Vol. 45, 223-231, February 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

The steroidal analog GW707 activates the SREBP pathway through disruption of intracellular cholesterol trafficking

Jessie Zhang*, Nicole Dudley-Rucker*, Jan R. Crowley{dagger}, Elvira Lopez-Perez§, Marc Issandou§, Jean E. Schaffer*,** and Daniel S. Ory*,{dagger}{dagger}

* Center for Cardiovascular Research, 91951 Les Ulis cedex, France
{dagger} Department of Internal Medicine, and Mass Spectrometry Facility, 91951 Les Ulis cedex, France
§ Department of Internal Medicine, Laboratoires GlaxoSmithKline, 91951 Les Ulis cedex, France
** Departments of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110-1010
{dagger}{dagger} Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110-1010

To whom correspondence should be addressed. e-mail: dory{at}wustl.edu

Recently, a new class of lipid-lowering agents has been described that upregulate LDL receptor (LDLr) activity. These agents are proposed to activate sterol-regulated gene expression through binding to the sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP). Here, we show that the steroidal LDLr upregulator, GW707, induces accumulation of lysosomal free cholesterol and inhibits LDL-stimulated cholesterol esterification, similar to that observed in U18666A-treated cells and in Niemann-Pick type C1 (NPC1) mutants. Moreover, we demonstrate that induction of the NPC-like phenotype by GW707 is independent of SCAP function. We find that treatment with GW707 does not increase SREBP-dependent gene expression above that observed in lipoprotein-starved cells. Rather, we show that the apparent increase in SREBP-dependent activity in GW707-treated cells is attributable to a failure to appropriately suppress sterol-regulated gene expression, as has been shown previously for U18666A-treated cells and NPC mutant fibroblasts. We further demonstrate that cells treated with either GW707 or U18666A fail to appropriately generate 27-hydroxycholesterol in response to LDL cholesterol.

Taken together, these findings support a mechanism in which GW707 exerts its hypolipidemic effects through disruption of late endosomal/lysosomal sterol trafficking and subsequent stimulation of LDLr activity.

Abbreviations: ER, endoplasmic reticulum; 25-HC, 25-hydroxycholesterol; 27-HC, 27-hydroxycholesterol; LDLr, LDL receptor; LPDS, lipoprotein-deficient serum; LXR, liver X receptor; NPC, Niemann-Pick type C; SRE, sterol regulatory element; SREBP, sterol regulatory element binding protein

Supplementary key words sterol regulatory element binding protein • cleavage-activating protein ligands • Niemann-Pick type C • sterol-sensing domain • 27-hydroxycholesterol


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


This article has been cited by other articles:


Home page
 GlycobiologyHome page
K. Mani, F. Cheng, and L.-A. Fransson
Defective nitric oxide-dependent, deaminative cleavage of glypican-1 heparan sulfate in Niemann-Pick C1 fibroblasts
Glycobiology, August 1, 2006; 16(8): 711 - 718.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
A. Davalos, C. Fernandez-Hernando, F. Cerrato, J. Martinez-Botas, D. Gomez-Coronado, C. Gomez-Cordoves, and M. A. Lasuncion
Red Grape Juice Polyphenols Alter Cholesterol Homeostasis and Increase LDL-Receptor Activity in Human Cells In Vitro
J. Nutr., July 1, 2006; 136(7): 1766 - 1773.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
D. S. Ory
Nuclear Receptor Signaling in the Control of Cholesterol Homeostasis: Have the Orphans Found a Home?
Circ. Res., October 1, 2004; 95(7): 660 - 670.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 All ASBMB Journals   Journal of Biological Chemistry 
 Molecular and Cellular Proteomics   ASBMB Today 
Copyright © 2004 by the American Society for Biochemistry and Molecular Biology.