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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, Elvira Lopez-Perez, Marc Issandou, Jean E. Schaffer^*,** and Daniel S. Ory^*,

^* Center for Cardiovascular Research, 91951 Les Ulis cedex, France
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
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

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