The cytochrome P450 epoxygenase pathway regulates the hepatic inflammatory response in fatty liver disease.

Robert N Schuck,Laura M Degraff,Kenneth B Tomer,Fred B Lih,Matthew L Edin,Zhenghong Xu,Artiom Gruzdev,H Michael Jones,Craig R Lee,Liza Makowski,Weibin Zha,Leaf Huang,Tricia M Miller,Samuel M Poloyac,Kimberly C Vendrov,Darryl C Zeldin

doi:10.1371/journal.pone.0110162

Abstract

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.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is a rapidly growing public health problem that is prevalent in approximately 30% of the United States general population [1]
Body weight did not change significantly from baseline (20.260.2 grams, p = 0.397) in response to the atherogenic diet; mice administered the standard diet experienced modest weight gain (1.260.2 grams, p,0.001). These data demonstrate that the atherogenic diet model induces hepatic lipid accumulation, inflammation, and injury, which are key drivers of the development and progression of NAFLD/non-alcoholic steatohepatitis (NASH), independent of weight gain
Using the atherogenic diet model of NAFLD/NASH, this study is the first to demonstrate that 1) induction of NAFLD/ NASH markedly and preferentially suppresses hepatic epoxyeicosatrienoic acids (EETs) biosynthesis and circulating EET levels through suppression of hepatic Cytochrome P450 (CYP) epoxygenase expression; and, 2) targeted disruption of Ephx2 restores hepatic and systemic EET levels and attenuates NAFLD/NASH-evoked hepatic inflammation and injury. These findings suggest that suppression of hepatic EET biosynthesis is a key pathological consequence of NAFLD/NASH, and therapeutic restoration of EET levels is an anti-inflammatory strategy with potential utility for the treatment of fatty liver disease-associated inflammation and injury

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a rapidly growing public health problem that is prevalent in approximately 30% of the United States general population [1]. NAFLD begins with simple steatosis, and may progress to non-alcoholic steatohepatitis (NASH), and to advanced fibrosis and cirrhosis of the liver [2]. The progression from NAFLD to NASH is poorly understood, the development and progression of hepatic inflammation is a key pathological mediator in this transition and is associated with the development of comorbid conditions [3,4]. Sustained activation of the hepatic inflammatory response drives macrophage infiltration into the liver, causing fibrosis and hepatic injury [6]. Consistent with this pathological progression of NAFLD/NASH, the high-fat/high-cholesterol ‘‘atherogenic’’ diet model of steatohepatitis induces dyslipidemia, hepatic inflammation, and fibrosis, through an innate immunemediated mechanism [7,8]

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