The Cytochrome P 450 Epoxygenase Pathway Regulates the Hepatic Inflammatory Response in Fatty Liver Disease

Fatty liver disease is an emerging public health problem without effective therapies, and chronic hepatic inflammation is a key pathologic mediator in its progression. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs), which have potent anti-inflammatory effects. Although promoting the effects of EETs elicits anti-inflammatory and protective effects in the cardiovascular system, the contribution of CYP-derived EETs to the regulation of fatty liver disease-associated inflammation and injury is unknown. Using the atherogenic diet model of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), our studies demonstrated that induction of fatty liver disease significantly and preferentially suppresses hepatic CYP epoxygenase expression and activity, and both hepatic and circulating levels of EETs in mice. Furthermore, mice with targeted disruption of Ephx2 (the gene encoding soluble epoxide hydrolase) exhibited restored hepatic and circulating EET levels and a significantly attenuated induction of hepatic inflammation and injury. Collectively, these data suggest that suppression of hepatic CYP-mediated EET biosynthesis is an important pathological consequence of fatty liver disease-associated inflammation, and that the CYP epoxygenase pathway is a central regulator of the hepatic inflammatory response in NAFLD/NASH. Future studies investigating the utility of therapeutic strategies that promote the effects of CYP-derived EETs in NAFLD/NASH are warranted. Citation: Schuck RN, Zha W, Edin ML, Gruzdev A, Vendrov KC, et al. (2014) The Cytochrome P450 Epoxygenase Pathway Regulates the Hepatic Inflammatory Response in Fatty Liver Disease. PLoS ONE 9(10): e110162. doi:10.1371/journal.pone. 0110162 Editor: Hervé Guillou, INRA, France Received June 20, 2014; Accepted September 8, 2014; Published October 13, 2014 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Funding: This publication was made possible by a grant from the NIH/NIGMS (R01GM088199) to Dr. Lee, a predoctoral training program in Integrative Vascular Biology supported by the NIH/NHLBI (T32HL069768) and a predoctoral fellowship from the American Heart Association (11PRE7240059) to Dr. Schuck, grants from the NIH/NINDS (R01NS052315) and NIH/NCRR (S10RR023461) to Dr. Poloyac, NIH/NIAAA (AA017376) to Dr. Makowski, NIH/NIDDK to the UNC Center for Gastrointestinal Biology and Disease (P30DK34987) and UNC Nutrition Obesity Research Center (P30DK056350), and funds from the Intramural Research Program of the NIH/NIEHS to Dr. Tomer (Z01ES050167) and Dr. Zeldin (Z01ES025034). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: Dr. Zeldin is a co-inventor on U.S. Patent No. 6,531,506 B1 (issued March 11, 2003) titled ‘‘Inhibition of Epoxide Hydrolases for the Treatment of Hypertension,’’ U.S. Patent No. 6,693,130 B2 (issued February 17, 2004) titled ‘‘Inhibition of Epoxide Hydrolases for the Treatment of Hypertension,’’ and U.S. Patent No. 6,916,843 B1 (issued July 12, 2005) titled ‘‘Anti-inflammatory Actions of Cytochrome P450 Epoxygenase-Derived Eicosanoids. ’’ No other authors have conflicts of interest to disclose. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials. * Email: craig_lee@unc.edu