The Cytochrome P450 Epoxygenase Pathway Regulates the Hepatic Inflammatory Response in Fatty Liver Disease

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.

Cytochrome P450-derived epoxyeicosatrienoic acids and coronary artery disease in humans: a targeted metabolomics study

“…Multiple preclinical studies have also demonstrated that CYP epoxygenase expression and EET biosynthesis are suppressed in the presence of pathological infl ammation. Notably, hepatic CYP epoxygenase expression, hepatic CYP epoxygenase metabolic function, and plasma EET levels were suppressed in an atherogenic diet mouse model of infl ammatory fatty liver disease ( 29 ). In contrast, no changes in sEH expression or EET hydrolysis were observed.…”

Characterization of the Cytochrome P450 epoxyeicosanoid pathway in non-alcoholic steatohepatitis

“…Free eicosanoid metabolite concentrations were quantified from mouse and human samples using a targeted liquid chromatography-tandem mass spectrometry (LC/MS/MS) method with optimized sensitivity and specificity for EET quantification, as previously described (11, 12, 20). Briefly, plasma/serum (0.25 mL) and homogenized liver (20 mg) and eWAT (50 mg) tissue were diluted in 0.1% acetic acid/5% methanol solution containing 0.009 mM butylated hydroxytoluene (BHT), and internal standards were added.…”

“…Due to significant correlations among the EET and DHET regioisomers (11, 12, 20), the sum of the EET regioisomers (sum EETs) and DHET regioisomers (sum DHETs) were calculated to minimize redundancy. The sum of the EET and DHET regioisomers (sum EETs+DHETs) and the ratio of 14,15-EET to 14,15-DHET (14,15-EET:14,15-DHET ratio) were calculated as biomarkers of CYP epoxygenase and sEH metabolic function, respectively.…”

“…CYP epoxygenase-derived EETs elicit cellular and organ protective effects in various preclinical models, including hypertension, ischemia-reperfusion injury and chemotherapy-induced organ injury, via attenuating inflammation, apoptosis and fibrosis (4–6). More recently, it has been reported that promoting the effects of EETs elicits protective effects in obesity-associated metabolic disease and in the atherogenic diet model of NAFLD/NASH in preclinical models (7–12). In addition, altered circulating CYP-derived DHET concentrations have been observed in humans diagnosed with NAFLD/NASH (13).…”

Role of Cytochrome P450s in Inflammation

“…Obesity was significantly correlated with low plasma EET levels in a clinical study (Theken et al, 2012). Multiple studies have associated increased EET levels with a reduction in inflammation and other symptoms of disease in rodent models of obesity and diabetes (Fleming, 2014), and fatty liver disease Schuck et al, 2014). CYP epoxygenase expression in locations such as liver, endothelial cells, pancreas, and mesenchymal stem cells is relevant to these activities.…”