Hepatocyte Peroxisome Proliferator-Activated Receptor Alpha Enhances Liver Regeneration After Partial Hepatectomy In Mice

Peroxisome proliferator activated receptor a (PPAR alpha) is a key nuclear receptor involved in the control of lipid homeostasis. In rodents, PPAR alpha is also a potent hepatic mitogen. Hepatocytespecific disruption of PPAR alpha inhibits agonist-induced hepatocyte proliferation; however, little is known about the exact role of PPAR alpha in partial hepatectomy (PHx) induced liver regeneration. Herein, using hepatocyte-specific PPAR alpha-deficient (Ppara(Delta HeP)) mice, the function of hepatocyte PPAR alpha in PHx-induced liver regeneration was investigated. PPAR alpha protein level and transcriptional activity were increased in the liver after PHx. Compared with the Ppara(fl/fl) mice, Ppara(Delta Hep) mice exhibited significantly reduced hepatocyte proliferation at 32 hours after PHx. Consistently, reduced Ccnd1 and Pcna mRNA and CYCD1 and proliferating cell nuclear antigen protein were observed at 32 hours after PHx in Ppara(Delta Hep) mice. Furthermore, Ppara(Delta Hep) mice showed increased hepatic lipid accumulation and enhanced hepatic triglyceride contents because of impaired hepatic fatty acid beta-oxidation when compared with that observed in Ppara(fl/fl) mice. These results indicate that PPAR alpha promotes liver regeneration after PHx, at least partially via regulating the cell cycle and lipid metabolism.