Nuclear Receptor PPAR alpha Agonist Wy-14,643 Ameliorates Hepatic Cell Death in Hepatic IKK beta-Deficient Mice

Abstract

Inhibitor of nuclear factor kappa-B kinase beta (IKK beta) plays a critical role in cell proliferation and inflammation in various cells by activating NE-kappa B signaling. However, the interrelationship between peroxisome proliferator-activated receptor alpha (PPAR alpha) and IKK beta in cell proliferation is not clear. In this study, we investigated the posible role of PPAR alpha, in the hepatic cell death in the absence of IKK beta gene using liver-specific Ikkb-null (Ikkb(F/F-AlbCre)) mice. To examine the function of PPAR alpha activation in hepatic cell death, wild-type (Ikkb(F/F)) and Ikkb(F/F-AlbCre) mice were treated with PPAR alpha agonist Wy-14,643 (0.1% w/w chow diet) for two weeks. As a result of Wy-14,643 treatment, apoptotic markers including caspase-3 cleavage, poly (ADP-ribose) polymerase (PARP) cleavage and TUNEL-positive staining were significantly decreased in the Ikkb(F/F-AlbCre) mice. Surprisingly, Wy-14,643 increased the phosphorylation of p65 and STAT3 in both Ikkb and Ikkb(F/F-AlbCre) mice. Furthermore, BrdU-positive cells were significantly increased in both groups after treatment with Wy-14,643. Our results suggested that IKK beta-derived hepatic apoptosis could be altered by PPAR alpha activation in conjunction with activation of NE-kappa B and STAT3 signaling.