Role of peroxisome proliferator-activated receptor-gamma (PPARgamma) during liver regeneration in rats.
OBJECTIVE
Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the nuclear receptor superfamily, is widely expressed in adipocytes and other tissues, including the liver. Several reports have shown that PPARgamma activation induced cell-cycle arrest and apoptosis in tumor cells. We investigated the role of the PPARgamma/ligand system and the effect of the PPARgamma agonist during liver regeneration.


METHODS
Expression of PPARgamma and serum levels of 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) by enzyme immunoassay were evaluated in rats following partial hepatectomy (PH group). Further, the effect of the PPARgamma 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 PPARgamma-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 PPARgamma 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 PPARgamma/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.
Department of Digestive and General Surgery, Faculty of Medicine, Shimane University, Enyacho, Izumo, Japan. yoshio55a@ybb.ne.jp
Yoshio
Y
Yamamoto
Takashi
T
Ono
Dipok Kumar
DK
Dhar
Akira
A
Yamanoi
Mitsuo
M
Tachibana
Tsuneo
T
Tanaka
Naofumi
N
Nagasue
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006498:Hepatectomy; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D023421:Models, Animal; D009369:Neoplasms / Q000188:drug therapy; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D000077205:Pioglitazone; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000494:pharmacology*
C477819:15-deoxyprostaglandin J2; D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D015230:Prostaglandin D2; D000077205:Pioglitazone