Soluble Epoxide Hydrolase Deficiency or Inhibition Attenuates Diet-induced Endoplasmic Reticulum Stress in Liver and Adipose Tissue

Soluble epoxide hydrolase (sEH) is a cytosolic enzyme whose inhibition has beneficial effects in cardiovascular, inflammatory, and metabolic diseases in murine models. Mice with targeted deletion or pharmacological inhibition of sEH exhibit improved insulin signaling in liver and adipose tissue. Her...

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Bibliographic Details
Published in:The Journal of biological chemistry 2013-05, Vol.288 (20), p.14189-14199
Main Authors: Bettaieb, Ahmed, Nagata, Naoto, AbouBechara, Daniel, Chahed, Samah, Morisseau, Christophe, Hammock, Bruce D., Haj, Fawaz G.
Format: Article
Language:English
Subjects:
3T3-L1 Cells
Adipose Tissue - metabolism
Animals
Cell Biology
Cytosol - enzymology
Diet
Endoplasmic Reticulum Stress
Epoxide Hydrolases - genetics
Epoxide Hydrolases - metabolism
Epoxyeicosatrienoic Acids (EETs)
Fatty Acids, Unsaturated - metabolism
Gene Expression Regulation
Hep G2 Cells
Humans
Hydrolases
Hydrolases - metabolism
Inflammation
Insulin - metabolism
Insulin Resistance
Liver - metabolism
Male
Metabolic Regulation
Metabolic Syndrome - metabolism
Mice
Mice, Inbred C57BL
Obesity - metabolism
Signal Transduction
Soluble Epoxide Hydrolase
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Summary:Soluble epoxide hydrolase (sEH) is a cytosolic enzyme whose inhibition has beneficial effects in cardiovascular, inflammatory, and metabolic diseases in murine models. Mice with targeted deletion or pharmacological inhibition of sEH exhibit improved insulin signaling in liver and adipose tissue. Herein, we assessed the role of sEH in regulating endoplasmic reticulum (ER) stress in liver and adipose tissue. We report that sEH expression was increased in the livers and adipose tissue of mice fed a high fat diet, the adipose tissue of overweight humans, and palmitate-treated cells. Importantly, sEH deficiency or inhibition in mice attenuated chronic high fat diet-induced ER stress in liver and adipose tissue. Similarly, pharmacological inhibition of sEH in HepG2 cells and 3T3-L1 adipocytes mitigated chemical-induced ER stress and activation of JNK, p38, and cell death. In addition, insulin signaling was enhanced in HepG2 cells treated with sEH substrates and attenuated in cells treated with sEH products. In summary, these findings demonstrate that sEH is a physiological modulator of ER stress and a potential target for mitigating complications associated with obesity. Background: Soluble epoxide hydrolase (sEH) is a cytosolic enzyme whose pharmacological inhibition or targeted deletion in mice has beneficial effects, including improved insulin signaling in liver and adipose tissue. Results: sEH inhibition or deficiency attenuates high fat diet- and chemical-induced endoplasmic reticulum (ER) stress in mice and cells, respectively. Conclusion: sEH modulates ER stress in a cell-autonomous manner. Significance: sEH may be a therapeutic target for mitigating complications associated with the metabolic syndrome.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M113.458414