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Journal of Lipid Research, Vol. 45, 223-231, February 2004 The steroidal analog GW707 activates the SREBP pathway through disruption of intracellular cholesterol trafficking
* Center for Cardiovascular Research, 91951 Les Ulis cedex, France
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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