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


ABSTRACT: Non-alcoholic steatohepatitis (NASH) is an emerging public health problem without effective therapies. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into bioactive epoxyeicosatrienoic acids (EETs), which have potent anti-inflammatory and protective effects. However, the functional relevance of the CYP epoxyeicosanoid metabolism pathway in the pathogenesis of NASH remains poorly understood. Our studies demonstrate that both mice with methionine-choline deficient (MCD) diet-induced NASH and humans with biopsy-confirmed NASH exhibited significantly higher free EET concentrations compared to healthy controls. Targeted disruption of Ephx2 (the gene encoding for soluble epoxide hydrolase) in mice further increased EET levels and significantly attenuated MCD diet-induced hepatic steatosis, inflammation and injury, as well as high fat diet-induced adipose tissue inflammation, systemic glucose intolerance and hepatic steatosis. Collectively, these findings suggest that dysregulation of the CYP epoxyeicosanoid pathway is a key pathological consequence of NASH in vivo, and promoting the anti-inflammatory and protective effects of EETs warrants further investigation as a novel therapeutic strategy for NASH.

SUBMITTER: Wells MA 

PROVIDER: S-EPMC5035202 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Wells Michael A MA   Vendrov Kimberly C KC   Edin Matthew L ML   Ferslew Brian C BC   Zha Weibin W   Nguyen Bobbie K H BK   Church Rachel J RJ   Lih Fred B FB   DeGraff Laura M LM   Brouwer Kim L R KL   Barritt A Sidney AS   Zeldin Darryl C DC   Lee Craig R CR  

Prostaglandins & other lipid mediators 20160709


Non-alcoholic steatohepatitis (NASH) is an emerging public health problem without effective therapies. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into bioactive epoxyeicosatrienoic acids (EETs), which have potent anti-inflammatory and protective effects. However, the functional relevance of the CYP epoxyeicosanoid metabolism pathway in the pathogenesis of NASH remains poorly understood. Our studies demonstrate that both mice with methionine-choline deficient (MCD) diet-induce  ...[more]

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