Critical role of diacylglycerol- and phospholipid-regulated protein kinase Cε in Induction of low-density lipoprotein receptor transcription in response to depletion of cholesterol

Kamal D. Mehta, Anna Radominska-Pandya, Gurpreet S. Kapoor, Bhuvanesh Dave, Brett A. Atkins

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Induction of low-density lipoprotein (LDL) receptor transcription in response to depletion of cellular sterols in animal cells is well established. The intracellular signal or signals involved in regulating this process, however, remain unknown. Using a specific inhibitor of protein kinase C (PKC), calphostin C, we show the requirement of this kinase in the induction process in human hepatoma HepG2 cells. Overexpression of PKCε, but not PKCα, -γ, -δ, or ζ was found to dramatically induce (approximately 18-fold) LDL receptor promoter activity. Interestingly, PKCε-mediated induction was found to be sterol resistant. To further establish that PKCε is involved in the sterol regulation of LDL receptor gene transcription, endogenous PKCε was specifically inhibited by transfection with antisense PKCε phosphorothionate oligonucleotides. Antisense treatment decreased endogenous PKCε protein levels and completely blocked induction of LDL receptor transcription following sterol depletion. PKCε-induced LDL receptor transcription is independent of the extracellular signal-regulated kinase 1 and 2 (p42/44MAPK) cascade, because the MEK-1/2 inhibitor, PD98059 did not inhibit, even though it blocked p42/44MAPK activation. Finally, photoaffinity labeling studies showed an isoform-specific interaction between PKCε and sterols, suggesting that sterols may directly modulate its function by hampering binding of activators. This was confirmed by PKC activity assays. Altogether, these results define a novel signaling pathway leading to induction of LDL receptor transcription following sterol depletion, and a model is proposed to account for a new function for PKCε as part of a sterol-sensitive signal transduction pathway in hepatic cells.

Original languageEnglish (US)
Pages (from-to)3783-3793
Number of pages11
JournalMolecular and Cellular Biology
Volume22
Issue number11
DOIs
StatePublished - 2002

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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