Role of peroxisome proliferator-activated receptor-gamma (PPARγ) during liver regeneration in rats

Background and Aim: Peroxisome proliferator-activated receptor-gamma (PPAR gamma), a member of the nuclear receptor superfamily, is widely expressed in adipocytes and other tissues, including the liver. Several reports have shown that PPAR gamma activation induced cell-cycle arrest and apoptosis in tumor cells. We investigated the role of the PPAR gamma/ligand system and the effect of the PPAR gamma agonist during liver regeneration. Methods: Expression of PPAR gamma and serum levels of 15-deoxy-Delta 12,14-prostaglandin J2 (15d-PGJ2) by enzyme immunoassay were evaluated in rats following partial hepatectomy (PH group). Further, the effect of the PPAR gamma agonist, pioglitazone, on liver regeneration (PH + PGZ group) was evaluated by proliferating cell nuclear antigen labeling index, relative liver weight, and expression of cell-cycle regulators. Results: The number of PPAR gamma-stained hepatocytes decreased at 24 h (PH, 15.8 +/- 2.2%; sham, 35.5 +/- 2.4%; P < 0.001) and increased in the late phase of liver regeneration compared to the sham-operated group (P < 0.001 at 48-120 h). The peaks of serum 15d-PGJ2 (627.0 +/- 91.1 pg/ml) and PPAR gamma expression (90.6 +/- 3.1%) coincided in the late phase of liver regeneration. Also, oral administration of pioglitazone inhibited hepatocyte proliferation, in terms of the proliferating cell nuclear antigen (PCNA) labeling index and p27 expression during the late phase of liver regeneration, and caused a transient reduction in liver mass when compared to the PH group. Conclusions: These results indicate that the PPAR gamma/ligand system may be one of the key negative regulators of hepatocyte proliferation and may be responsible for the inhibition of liver growth in the late phase of liver regeneration.