Activation of peroxisome proliferator-activated receptor-α in mice induces expression of the hepatic low-density lipoprotein receptor

Z. Huang, X. Zhou, A. C. Nicholson, A. M. Gotto, D. P. Hajjar, J. Han

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Background and purpose: Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolaemia in humans and deletion of the LDLR induces lesion development in mice fed a high-fat diet. LDLR expression is predominantly regulated by sterol regulatory element-binding protein 2 (SREBP2). Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) ligand, belongs to a drug class used to treat dyslipidaemic patients. We have investigated the effects of fenofibrate on hepatic LDLR expression. Experimental approach: The effects of fenofibrate on hepatic LDLR expression (mRNA and protein) and function were evaluated by both in vitro (with AML12 cells) and in vivo experiments in mice. Key results: Fenofibrate increased LDLR expression and LDL binding in a mouse hepatoma cell line, AML12 cells. Fenofibrate restored sterol-inhibited hepatocyte LDLR expression. Mechanistic studies demonstrated that induction of LDLR expression by fenofibrate was dependent on PPARα and sterol regulatory elements (SRE). Specifically, fenofibrate induced LDLR expression by increasing maturation of SREBP2 and phosphorylation of protein kinase B (Akt) but had no effect on SREBP cleavage-activating protein. In vivo, a high-fat diet suppressed LDLR expression in mouse liver while elevating total and LDL cholesterol levels in plasma. However, fenofibrate restored LDLR expression inhibited by high-fat diets in the liver and reduced LDL cholesterol levels in plasma. Conclusions and implications: Our data suggest that fenofibrate increased hepatic LDLR expression in mice by a mechanism involving Akt phosphorylation and LDLR gene transcription mediated by SREBP2.

Original languageEnglish (US)
Pages (from-to)596-605
Number of pages10
JournalBritish Journal of Pharmacology
Volume155
Issue number4
DOIs
StatePublished - Oct 2008

Keywords

  • Akt
  • Fenofibrate
  • LDLR
  • PPARα
  • SREBP2

ASJC Scopus subject areas

  • Pharmacology

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