Nuclear receptor peroxisome proliferator-activated receptor alpha protects the liver from LPS-induced hepatic apoptosis

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NCI	IMMUNO/INFLAM-2

* FARE Award Winner

Authors

• J Bonzo
• A Patterson
• Y Shah
• F Gonzalez

Abstract

Fulminant hepatic failure most commonly results from exposure to viral hepatitis or hepatotoxicants. Except for acetaminophen overdose, there are few proactive treatments available to prevent further liver deterioration. The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARa) is known to regulate lipid homeostasis and the synthetic fibrate PPARa ligand WY14643 has recently been identified as anti-inflammatory. Given the significant role PPARa plays in liver homeostasis, in particular mitochondrial function, we hypothesized WY14643 treatment would be protective in the LPS/GalN mouse model of fulminant hepatitis. Pretreatment of mice with WY14643 prevented LPS-induced liver injury as measured by histology score and serum ALT and AST levels. Mitochondrial GSH depletion and subsequent increase in H2O2 after LPS treatment was similarly blocked with WY treatment. The protective effect of WY14643 is dependent on Ppara expression as LPS-treated Ppara-null mice displayed liver injury equivalent to LPS-treated wild-type mice. JNK activation by LPS stimulation was blunted with WY14643 cotreatment indicating a reduction in inflammatory and apoptotic signals through Tnfr1 through Tnfr1 signaling. The identification of a well-tolerated, commonly prescribed class of drugs, fibrates, as protective in a model of fulminant hepatitis provides new possibilities for active intervention to prevent further hepatic deterioration in patients.

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