Rosiglitazone inhibits mouse liver regeneration.
The remarkable regenerative potential of the liver is well known. Recent investigations have shown that this regenerative response is impaired in mouse models of fatty liver disease. Other studies demonstrate that mice engineered for liver-specific overexpression of the peroxisome proliferator activated receptor gamma (PPARgamma) develop significant hepatic steatosis. These observations suggest that precise regulation of hepatic PPARgamma activity may be essential for normal liver regeneration. To test this hypothesis, we analyzed the effects of PPARgamma-activating thiazolidinediones on liver regeneration in the rodent partial hepatectomy model. Thiazolidinediones with different PPARgamma-activating potencies were administered to mice, and those mice were subjected to partial hepatectomy and analyzed for resulting effects on hepatocellular proliferation and signaling pathways important during normal liver regeneration. The results showed that thiazolidinediones suppress liver regeneration with efficacies that correlate with their relative PPARgamma-activating potencies. These studies provide the first evidence linking regulation of PPARgamma activity and the hepatic regenerative response.
Turmelle
Yumirle P
YP
Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
Shikapwashya
Olga
O
Tu
Shu
S
Hruz
Paul W
PW
Yan
Qingyun
Q
Rudnick
David A
DA
D000818:Animals; D002839:Chromans / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D015850:Interleukin-6 / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000378:metabolism; D000077154:Rosiglitazone; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C493957:Cdkn1a protein, mouse; D002839:Chromans; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015850:Interleukin-6; D047495:PPAR gamma; D012333:RNA, Messenger; D044786:S-Phase Kinase-Associated Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D000077154:Rosiglitazone; D050760:Cyclin-Dependent Kinase Inhibitor p27; D048051:p38 Mitogen-Activated Protein Kinases; D000077288:Troglitazone; D000077205:Pioglitazone