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Nuclear Receptor PPARα Agonist Wy-14,643 Ameliorates Hepatic Cell Death in Hepatic IKKβ-Deficient Mice
Taehyeong Kim1, Lilik Duwi Wahyudi2, Frank J Gonzalez1
1Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Abstract:
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.
Insights
Peroxisome proliferator-activated receptor α (PPARα) activation reduces liver cell death in mice lacking inhibitor of nuclear factor kappa-B kinase beta (IKKβ). PPARα also activates NF-κB and STAT3 signaling, promoting cell proliferation.
Area of Science:
- Molecular Biology
- Hepatology
- Cell Signaling
Background:
- Inhibitor of nuclear factor kappa-B kinase beta (IKKβ) is crucial for NF-κB signaling, impacting cell proliferation and inflammation.
- The relationship between peroxisome proliferator-activated receptor α (PPARα) and IKKβ in regulating cell proliferation remains unclear.
Purpose of the Study:
- To investigate the role of PPARα in hepatic cell death in mice lacking the IKKβ gene.
- To determine the effect of PPARα activation on NF-κB and STAT3 signaling pathways in the liver.
Main Methods:
- Utilized liver-specific Ikkb-null (IkkbF/F-AlbCre) and wild-type (IkkbF/F) mice.
- Administered PPARα agonist Wy-14,643 via diet for two weeks.
- Assessed apoptotic markers (caspase-3, PARP cleavage, TUNEL staining), p65 and STAT3 phosphorylation, and cell proliferation (BrdU incorporation).
Main Results:
- Wy-14,643 treatment significantly decreased apoptotic markers in IkkbF/F-AlbCre mice.
- PPARα activation increased p65 and STAT3 phosphorylation in both wild-type and Ikkb-null mice.
- BrdU-positive cells, indicating proliferation, were significantly increased in both genotypes following Wy-14,643 treatment.
Conclusions:
- PPARα activation can mitigate IKKβ-dependent hepatic apoptosis.
- PPARα activation influences hepatic cell fate by modulating NF-κB and STAT3 signaling pathways.
- The findings suggest a complex interplay between PPARα, IKKβ, and cell survival/proliferation in the liver.
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