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Nuclear Receptor PPARα Agonist Wy-14,643 Ameliorates Hepatic Cell Death in Hepatic IKKβ-Deficient Mice  

Kim, Taehyeong (Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health)
Wahyudi, Lilik Duwi (Department of Pharmacology and Graduate School of Convergence Medical Science, School of Medicine, Institute of Health Sciences, Gyeongsang National University)
Gonzalez, Frank J. (Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health)
Kim, Jung-Hwan (Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health)
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Biomolecules & Therapeutics / v.25, no.5, 2017 , pp. 504-510 More about this Journal
Inhibitor of nuclear factor kappa-B kinase beta ($IKK{\beta}$) plays a critical role in cell proliferation and inflammation in various cells by activating $NF-{\kappa}B$ 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 possible 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 $NF-{\kappa}B$ and STAT3 signaling.
PPARa; IKKb; NF-kB; Wy-14,643; STAT3;
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