title: Prevention of steatohepatitis by pioglitazone: implication of adiponectin-dependent inhibition of SREBP-1c and inflammation.
abstract: OBJECTIVE
  Peroxisome proliferator-activated receptor gamma (PPARgamma) agonist drugs, like pioglitazone (PGZ), are proposed as treatments for steatohepatitis. Their mechanisms of action remain ill-clarified.
  
  
  METHODS
  To test the hypothesis that PGZ improves steatohepatitis through adiponectin-dependent stimulation of AMPK and/or PPARalpha, mice lacking adiponectin (Adipo(-/-)) or the AMPKalpha1 catalytic subunit (AMPKalpha1(-/-)) or wild-type (Wt) mice were fed the methionine and choline deficient (MCD) diet, supplemented or not with PGZ.
  
  
  RESULTS
  In Wt mice, PGZ increased circulating levels of adiponectin and reduced the severity of MCD-induced steatohepatitis but there was no evidence of activation of AMPK or PPARalpha and their downstream targets. By contrast, PGZ completely repressed nuclear translocation of SREBP-1c, a key transcription factor for de novo lipogenesis. This effect was lacking in Adipo(-/-) mice in which PGZ failed to prevent steatohepatitis. Surprisingly, AMPKalpha1(-/-) mice were resistant to MCD-induced steatohepatitis, a status also associated with repression of SREBP-1c.
  
  
  CONCLUSIONS
  The preventive effect of PGZ on MCD-induced steatohepatitis depends on adiponectin upregulation but apparently does not involve AMPK or PPARalpha activation. The inhibition of SREBP-1c and dependent repression of lipogenesis are likely to participate in this effect. The mechanisms by which PGZ and adiponectin control SREBP-1c and inflammation remain to be elucidated.
authors.affiliation: Laboratoire de Gastro-entérologie, Université Catholique de Louvain, GAEN 53/79, Brussels, Belgium.
authors.forename: Alain
authors.initials: A
authors.lastname: Da Silva Morais
authors.forename: Valérie
authors.initials: V
authors.lastname: Lebrun
authors.forename: Jorge
authors.initials: J
authors.lastname: Abarca-Quinones
authors.forename: Sonia
authors.initials: S
authors.lastname: Brichard
authors.forename: Louis
authors.initials: L
authors.lastname: Hue
authors.forename: Bruno
authors.initials: B
authors.lastname: Guigas
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Isabelle A
authors.initials: IA
authors.lastname: Leclercq
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D052242:Adiponectin / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D002796:Choline Deficiency / Q000150:complications; D017931:DNA Primers; D005234:Fatty Liver / Q000517:prevention & control*; D005260:Female; D007249:Inflammation / Q000517:prevention & control*; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000077205:Pioglitazone; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D045162:Thiazolidinediones / Q000627:therapeutic use*
chemical_list: D052242:Adiponectin; D017931:DNA Primers; D051780:Sterol Regulatory Element Binding Protein 1; D045162:Thiazolidinediones; D012313:RNA; D008715:Methionine; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D000077205:Pioglitazone