title: Anti-adipogenic action of pitavastatin occurs through the coordinate regulation of PPARgamma and Pref-1 expression.
abstract: OBJECTIVE
  Adipocyte differentiation in vitro is coordinately activated by two transcription factors, peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT enhancer binding protein alpha (C/EBPalpha), 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.
  
  
  METHODS
  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 PPARgamma, C/EBPalpha and pref-1 expression.
  
  
  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 PPARgamma expression, but not C/EBPalpha expression or DNA binding activity of PPARgamma. Also, pitavastatin induced pref-1 expression in preadipocytes and maintained expression of pref-1 at high levels in differentiated cells.
  
  
  CONCLUSIONS
  Our data suggest that pitavastatin inhibits adipocyte differentiation by blocking PPARgamma expression and activating pref-1 expression. These studies may have implications in the regulation of adipogenesis in response to statins.
authors.affiliation: Department of Pathology, Center of Vascular Biology, Weill Medical College of Cornell University, New York, NY 10021, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Nicholson
authors.forename: D P
authors.initials: DP
authors.lastname: Hajjar
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.forename: W
authors.initials: W
authors.lastname: He
authors.forename: A M
authors.initials: AM
authors.lastname: Gotto
authors.forename: J
authors.initials: J
authors.lastname: Han
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001391:Azo Compounds; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005786:Gene Expression Regulation; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D047495:PPAR gamma / Q000187:drug effects* / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D014158:Transcription, Genetic; D014280:Triglycerides
chemical_list: D001391:Azo Compounds; D022763:CCAAT-Enhancer-Binding Protein-alpha; D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D047495:PPAR gamma; D011804:Quinolines; D014280:Triglycerides; D004247:DNA; C011049:oil red O; C108475:pitavastatin