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, Daniel S. Ory

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

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) deavage-activating protein (SCAP). Here, we show that the steroidal LDLr upregulator, GW707, induces accumulation of lysosomal free cholesterol and inhibits LDL-simulated 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.

Original languageEnglish
Pages (from-to)223-231
Number of pages9
JournalJournal of lipid research
Volume45
Issue number2
DOIs
StatePublished - Feb 1 2004

Keywords

  • 27-hydroxycholesterol
  • Cleavage-activating protein ligands
  • Niemann-Pick type C
  • Sterol regulatory element binding protein
  • Sterol-sensing domain

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