title: Pioglitazone promotes survival and prevents hepatic regeneration failure after partial hepatectomy in obese and diabetic KK-A(y) mice.
abstract: Pathogenesis of metabolic syndrome-related nonalcoholic steatohepatitis (NASH) involves abnormal tissue-repairing responses in the liver. We investigated the effect of pioglitazone, a thiazolidinedione derivative (TZD), on hepatic regenerative responses in obese, diabetic KK-A(y) mice. Male KK-A(y) mice 9 weeks after birth underwent two-thirds partial hepatectomy (PH) after repeated intragastric injections of pioglitazone (25 mg/kg) for 5 days. Almost half of the KK-A(y) mice died within 48 hours of PH;however, mortality was completely prevented in mice pretreated with pioglitazone. In KK-A(y) mice, bromodeoxyuridine (BrdU) incorporation to hepatocyte nuclei 48 hours after PH reached only 1%; however, pioglitazone pretreatment significantly increased BrdU-positive cells to 8%. Cyclin D1 was barely detectable in KK-A(y) mice within 48 hours after PH. In contrast, overt expression of cyclin D1 was observed 24 hours after PH in KK-A(y) mice pretreated with pioglitazone. Hepatic tumor necrosis factor alpha (TNF-alpha) messenger RNA (mRNA) was tremendously increased 1 hour after PH in KK-A(y) mice, the levels reaching ninefold over C57Bl/6 given PH, whereas pioglitazone blunted this increase by almost three-fourths. Pioglitazone normalized hypoadiponectinemia in KK-A(y) mice almost completely. Serum interleukin (IL)-6 and leptin levels were elevated extensively 24 hours after PH in KK-A(y) mice, whereas the levels were largely decreased in KK-A(y) mice given pioglitazone. Indeed, pioglitazone prevented aberrant increases in signal transducers and activators of transcription (STAT)3 phosphorylation and suppressor of cytokine signaling (SOCS)-3 mRNA in the liver in KK-A(y) mice.
  
  
  CONCLUSIONS
  These findings indicated that pioglitazone improved hepatic regeneration failure in KK-A(y) mice. The mechanism underlying the effect of pioglitazone on regeneration failure most likely involves normalization of expression pattern of adipokines and subsequent cytokine responses during the early stage of PH.
authors.affiliation: Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Aoyama
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ikejima
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kon
authors.forename: Kyoko
authors.initials: K
authors.lastname: Okumura
authors.forename: Kumiko
authors.initials: K
authors.lastname: Arai
authors.forename: Sumio
authors.initials: S
authors.lastname: Watanabe
mesh_terms: D054392:Adipokines / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose; D048909:Diabetes Complications / Q000188:drug therapy / Q000378:metabolism; D006498:Hepatectomy; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007333:Insulin Resistance; D053612:Janus Kinases / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists; D010766:Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D054392:Adipokines; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D045162:Thiazolidinediones; D053612:Janus Kinases; D000077205:Pioglitazone