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American Liver Foundation
39 Broadway, Suite 2700
New York, New York 10006
Roger L. Jenkins, MD Postdoctoral Research Fellowship
Pennsylvania State University, State College, Pennsylvania
Targeting PPARβ/δ to Inhibit Hepatic Inflammation
Liver cancer is the most rapidly increasing type of cancer. Increased inflammation can modulate hepatocarcinogenesis whereas anti-inflammatory compounds can inhibit liver cancer. Targeting peroxisome proliferator-activated receptor β/δ (PPARβ/δ) can modulate cellular homeostasis and result in epigenetic activities such as inhibition of expression of proinflammatory cytokines. Dr. Palkar hypothesizes that PPARβ/δ attenuates hepatic inflammation by modulating NF-κB dependent inflammatory signaling in Kupffer cells. Preliminary results indicate that PPARβ/δ protects against hepatotoxicity, likely by direct interaction of PPARβ/δ with NF-κB and inhibition of pro-inflammatory signaling. To examine this hypothesis, Dr. Palkar will use transgenic mice with DNA binding mutations on PPARβ/δ in Kupffer cells. Mice will be injected with lipopolysaccharide ± the highly specific PPARβ/δ agonist, GW0742. Markers of inflammation will be evaluated and chromatin immunoprecipitation assays performed to provide direct mechanistic evidence for how PPARβ/δ can attenuate hepatic inflammation. The proposed studies using the mouse models will determine if epigenetic modulation of PPARβ/δ can protect against hepatic inflammation in vivo. Results from Dr. Palkar’s proposal will also determine if PPARβ/δ can be used as an anti-inflammatory molecular target and as an alternative strategy for preventing and treating inflammatory liver diseases.