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The cytochrome p450 epoxygenase pathway regulates the hepatic inflammatory response in fatty liver disease

Schuck, RN and Zha, W and Edin, ML and Gruzdev, A and Vendrov, KC and Miller, TM and Xu, Z and Lih, FB and DeGraff, LM and Tomer, KB and Jones, HM and Makowski, L and Huang, L and Poloyac, SM and Zeldin, DC and Lee, CR (2014) The cytochrome p450 epoxygenase pathway regulates the hepatic inflammatory response in fatty liver disease. PLoS ONE, 9 (10).

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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.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Schuck, RN
Zha, W
Edin, ML
Gruzdev, A
Vendrov, KC
Miller, TM
Xu, Z
Lih, FB
DeGraff, LM
Tomer, KB
Jones, HM
Makowski, L
Huang, L
Poloyac, SM
Zeldin, DC
Lee, CR
ContributionContributors NameEmailPitt UsernameORCID
Date: 13 October 2014
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 9
Number: 10
DOI or Unique Handle: 10.1371/journal.pone.0110162
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Refereed: Yes
Other ID: NLM PMC4195706
PubMed Central ID: PMC4195706
PubMed ID: 25310404
Date Deposited: 12 May 2015 18:23
Last Modified: 13 Oct 2017 22:55


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