The steroidal analog GW707 activates the SREBP pathway through disruption of intracellular cholesterol trafficking.
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.
Zhang
Jessie
J
Center for Cardiovascular Research, 91951 Les Ulis, France.
Dudley-Rucker
Nicole
N
Crowley
Jan R
JR
Lopez-Perez
Elvira
E
Issandou
Marc
M
Schaffer
Jean E
JE
Ory
Daniel S
DS
D000736:Androstenes / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells / Q000166:cytology; D002784:Cholesterol / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009542:Niemann-Pick Diseases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011973:Receptors, LDL / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013256:Steroids / Q000494:pharmacology*; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors
D000736:Androstenes; D022762:CCAAT-Enhancer-Binding Proteins; D008078:Cholesterol, LDL; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C442817:GW 707; D011973:Receptors, LDL; D011994:Recombinant Proteins; D013256:Steroids; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D002784:Cholesterol; D008156:Luciferases