Anti-adipogenic action of pitavastatin occurs through the coordinate regulation of PPARγ and Pref-1 expression

A. C. Nicholson, D. P. Hajjar, X. Zhou, W. He, A. M. Gotto, J. Han

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Background and purpose: Adipocyte differentiation in vitro is coordinately activated by two transcription factors, peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT enhancer binding protein α (C/EBPα), but it is inhibited by preadipocyte factor-1 (pref-1). Statins, inhibitors of HMG-CoA reductase and de novo cholesterol synthesis, can have pleiotropic effects which influence adipocyte phenotype by ill-defined mechanisms. We investigated the effects of pitavastatin (NK-104) on adipocyte differentiation and the transcriptional pathways involved. Experimental approach: The effects of pitavastatin on adipocyte differentiation were evaluated by the formation of oil droplets, content of cellular triglyceride and expression of adipocyte-specific genes. Regulatory mechanisms were assessed by analysis of PPARγ, C/EBPα and pref-1 expression. Key results: Pitavastatin significantly inhibited adipocyte differentiation of 3T3-L1 preadipocytes in response to adipogenic inducers. Evidence for inhibition included fewer Oil Red O positive droplets, less cellular triglyceride and decreased expression of adipocyte-specific genes, including fatty acid binding protein (aP2), CD36, adipsin and glucose transporter 4 (GLUT4). The inhibitory effects of pitavastatin on adipocyte differentiation of 3T3-L1 preadipocytes were time and concentration dependent. Pitavastatin significantly blocked induction of PPARγ expression, but not C/EBPα expression or DNA binding activity of PPARγ. Also, pitavastatin induced pref-1 expression in preadipocytes and maintained expression of pref-1 at high levels in differentiated cells. Conclusions and implications: Our data suggest that pitavastatin inhibits adipocyte differentiation by blocking PPARγ expression and activating pref-1 expression. These studies may have implications in the regulation of adipogenesis in response to statins.

Original languageEnglish (US)
Pages (from-to)807-815
Number of pages9
JournalBritish Journal of Pharmacology
Volume151
Issue number6
DOIs
StatePublished - Jul 2007

Keywords

  • Adipocyte differentiation
  • C/EBPα
  • Fibroblasts
  • Pitavastatin
  • PPARγ
  • Pref-1
  • Triglycerides

ASJC Scopus subject areas

  • Pharmacology

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