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Epoxyeicosatrienoic Acid May Be a Biomarker for Nonalcoholic Steatohepatitis

Key findings

  • Preclinical research has demonstrated that epoxyeicosatrienoic acid (EET), which is metabolized to dihydroxyeicosatrienoic acid (DHET), protects against nonalcoholic steatohepatitis (NASH)
  • This study demonstrated inverse associations between circulating EET/DHET and the prevalence and severity of nonalcoholic fatty liver disease (NAFLD) and NASH
  • Cytochrome P450 epoxygenase function (which converts arachidonic acid into EET) progressively declined with worsening NASH fibrosis and distinguished NASH from steatosis
  • Soluble epoxide hydrolase function (which metabolizes EET into DHET) was not significantly associated with NAFLD prevalence or severity
  • EET augmentation should be explored as a therapy for NAFLD

Nearly 25% of patients with nonalcoholic fatty liver disease (NAFLD) develop nonalcoholic steatohepatitis (NASH), which accelerates progression to fibrosis and cirrhosis. Unfortunately, there are no reliable noninvasive ways to identify patients who are at high risk of NASH.

Both in vitro and in vivo research suggests that epoxyeicosatrienoic acid (EET) protects against NASH. Four biologically active EETs are generated from arachidonic acid by cytochrome P450 (CYP) epoxygenases, and they are further metabolized to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase.

Ashwini Arvind, MBBS, MPH, research fellow in the Department of Medicine at Massachusetts General Hospital, Tracey G. Simon, MD, MPH, hepatologist in the Division of Gastroenterology, and colleagues recently became the first to study EET metabolites across the spectrum of NAFLD. In Gastroenterology, they report that circulating EET was significantly associated with NAFLD prevalence and severity.

Study Details

Since 2010, the prospective Mass General NAFLD Repository has enrolled adults with histologically confirmed NAFLD and non-NAFLD controls. For this cross-sectional analysis, the researchers identified four groups of age- and sex-matched subjects (20 per group):

  • Non-NAFLD controls
  • Steatosis
  • NASH with fibrosis stage 0–2
  • NASH with fibrosis stage 3–4

Using state-of-the-art liquid chromatography-tandem mass spectrometry, the team measured 11,12-EET, 14,15-EET, total EET, 11,12-DHET, 14,15-DHET, total DHET, CYP epoxygenase function (EET+DHET) and soluble epoxide hydrolase function (the ratio of 14,15-EET to 14,15-DHET).

Circulating EET and DHET

On multivariable analysis:

  • Total EET and total DHET were significantly lower in the steatosis group and both NASH groups than in controls (all comparisons P < .05)
  • Total EET and total DHET were significantly lower in both NASH groups than in the steatosis group (all comparisons P < .05)

Other Exposures

CYP epoxygenase function was significantly lower in the NAFLD groups (steatosis or NASH) than in controls (P = .002). In the NAFLD groups, CYP epoxygenase function declined significantly as NASH severity increased (P = .01). CYP epoxygenase function was 93% accurate in distinguishing NASH cases from steatosis.

Soluble epoxide hydrolase function did not differ significantly between NAFLD and controls or with worsening NAFLD severity.

Clinical Relevance

These findings suggest that EET depletion in NAFLD may result from suppressed EET synthesis. Circulating EET may be a biomarker for NASH, and EET augmentation should be explored as a therapy for NAFLD.

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