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


     

A more recent version of this article appeared on February 1, 2004

Papers In Press, published online ahead of print November 16, 2003
J. Lipid Res., doi:10.1194/jlr.M300409-JLR200
This Article
Right arrow Full Text (Accepted Manuscript)
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
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?

Submitted on September 26, 2003
Revised on October 31, 2003
Accepted on November 3, 2003

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

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

Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110

Corresponding Author: dory{at}wustl.edu

Recently, a new class of lipid-lowering agents has been described that up-regulate LDL receptor activity (LDLr). 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 up-regulator, GW707, induces accumulation of lysosomal free cholesterol and inhibits low-density lipoprotein (LDL)-stimulated cholesterol esterification, similar to that observed in U18666A-treated cells and in Niemann-Pick 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 due 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 hypolidemic effects through disruption of late endosomal/lysosomal sterol trafficking and subsequent stimulation of LDLr activity.


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
 All ASBMB Journals   Journal of Biological Chemistry 
 Molecular and Cellular Proteomics   ASBMB Today 
Copyright © 2003 by the American Society for Biochemistry and Molecular Biology.