Biomolecules & Therapeutics  
Nuclear Receptor PPARα Agonist Wy-14,643 Ameliorates Hepatic Cell Death in Hepatic IKKβ-Deficient Mice
Taehyeong Kim1, Lilik Duwi Wahyudi2, Frank J. Gonzalez1 and Jung-Hwan Kim1,2,*
1Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA, 2Department of Pharmacology and Graduate School of Convergence Medical Science, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 52727, Republic of Korea
Tel: +82-55-772-8072, Fax: +82-55-772-8079
Received: September 22, 2016; Revised: November 15, 2016; Accepted: December 6, 2016; Published online: February 13, 2017.
© The Korean Society of Applied Pharmacology. All rights reserved.

Inhibitor of nuclear factor kappa-B kinase beta (IKKβ) plays a critical role in cell proliferation and inflammation in various cells by activating NF-κB signaling. However, the interrelationship between Peroxisome proliferator-activated receptor α (PPARα) and IKKβ in cell proliferation is not clear. In this study, we investigated the possible role of PPARα in the hepatic cell death in the absence of IKKβ gene using liver-specific Ikkb-null (IkkbF/F-AlbCre) mice. To examine the function of PPARα activation in hepatic cell death, wild-type (IkkbF/F) and IkkbF/F-AlbCre mice were treated with PPARα 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 IkkbF/F-AlbCre mice. Surprisingly, Wy-14,643 increased the phosphorylation of p65 and STAT3 in both Ikkb and IkkbF/F-AlbCre mice. Furthermore, BrdU-positive cells were significantly increased in both groups after treatment with Wy-14,643. Our results suggested that IKKβ-derived hepatic apoptosis could be altered by PPARα activation in conjunction with activation of NF-κB and STAT3 signaling.
Keywords: PPARa, IKKb, NF-kB, Wy-14,643, STAT3
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