Peroxisome proliferator-activated receptor α (PPARα) plays a critical role in lipid metabolism, inflammation, carcinogenesis, and cell survival. Recent study showed that PPARα agonist dramatically induced the cell cycle arrest genes, such as p21 and Gadd45b, in the liver of mice. However, the inductions of these genes were not lead to hepatic cell death. Thus, here, we investigated the Ikkb gene whether this can affect the hepatic cell death or survival after induction of p21 and Gadd45b. To exam the function of Ikkb after PPARα activation, the Wild-type (IkkbF/F) and liver-specific Ikkb-null (IkkbF/F-AlbCre) mice were treated with the PPARα agonist Wy-14,643 for two weeks. As results, Hepatic cell death was undergone to apoptosis by increases of cleaved-caspase-3 and cleaved poly (ADP-ribose) polymerase only in the liver of IkkbF/F-AlbCre mice by Wy-14,643 and this was also supported by TUNEL staining. Moreover, Wy-14,643 treatment elevated phosphorylation of c-Jun N-terminal kinase only in the liver of IkkbF/F-AlbCre mice. Liver histology showed notable feature of hepatitis only in the IkkbF/F-AlbCre mice treated with Wy-14,643. And marked increase Tnfa mRNA was followed in Wy-14,643-treated IkkbF/F-AlbCre mice. However, expression of the gene related to lipid metabolism such as Ppara and Acox1 were not significantly changed by Wy-14,163 in both IkkbF/F and IkkbF/F-AlbCre mice. These studies suggest that Ikkb gene may play a critical role in hepatic cell survival against PPARα activation.

Citation Format: Jung-Hwan Kim, Taehyeong Kim, Aijuan Qu, Frank J. Gonzalez. Nuclear receptor PPARα activation triggers hepatic cell death in Ikkβ-deficient mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 23. doi:10.1158/1538-7445.AM2015-23