Pioglitazone Promotes Survival and Prevents Hepatic Regeneration Failure After Partial Hepatectomy in Obese and Diabetic KK-Ay Mice

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, bromodeoxyuidine (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 C57B1/6 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. Conclusion: 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. (HEPATOLOGY 2009; 49:1636-1644.)