The Hypocholesterolemic Agent LY295427 Reverses Suppression of Sterol Regulatory Element-binding Protein Processing Mediated by Oxysterols

Bethany A. Janowski, Bei Shan, David W. Russell

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

The sterol LY295427 reduces plasma cholesterol levels in animals by increasing the expression of hepatic low density lipoprotein (LDL) receptors. Here we trace the hypocholesterolemic activity of LY295427 to an ability to reverse oxysterol-mediated suppression of sterol regulatory element-binding protein (SREBP) processing. Micromolar concentrations of LY295427 induced the metabolism of LDL in oxysterol-treated cultured cells and inhibited the stimulation of cholesteryl ester synthesis mediated by oxysterols. cDNA microarray and RNA blotting experiments revealed that LY295427 increased levels of the LDL receptor mRNA and those of other SREBP target genes. The compound stimulated the accumulation of SREBPs in the nuclei of cells grown in the presence of oxysterols within 4-6 h of addition to the medium. Induction required components of the normal SREBP-processing pathway, including the SREBP cleavage-activating protein and the Site 1 protease. LY295427 overcame the suppression of SREBP processing mediated by several oxysterols but not by LDL-derived cholesterol. We conclude that LY295427 achieves a therapeutically desirable end point by an unique mechanism of action.

Original languageEnglish (US)
Pages (from-to)45408-45416
Number of pages9
JournalJournal of Biological Chemistry
Volume276
Issue number48
DOIs
StatePublished - Nov 30 2001

Fingerprint

LY 295427
Sterol Regulatory Element Binding Proteins
Processing
LDL Receptors
LDL Lipoproteins
Cholesterol
Cells
Cholesterol Esters
Sterols
Microarrays
Metabolism
Oligonucleotide Array Sequence Analysis
Cell Nucleus
Animals
LDL Cholesterol
Complementary DNA
Genes
Oxysterols
Cultured Cells
RNA

ASJC Scopus subject areas

  • Biochemistry

Cite this

The Hypocholesterolemic Agent LY295427 Reverses Suppression of Sterol Regulatory Element-binding Protein Processing Mediated by Oxysterols. / Janowski, Bethany A.; Shan, Bei; Russell, David W.

In: Journal of Biological Chemistry, Vol. 276, No. 48, 30.11.2001, p. 45408-45416.

Research output: Contribution to journalArticle

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