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

Bettaieb, Ahmed; Nagata, Naoto; AbouBechara, Daniel; Chahed, Samah; Morisseau, Christophe; Hammock, Bruce D.; Haj, Fawaz G.

doi:10.1074/jbc.m113.458414

Cited by 112 publications

(147 citation statements)

References 66 publications

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“…ER stress is implicated in AP (Kubisch et al, 2006;Seyhun et al, 2011;Malo et al, 2013). Given the capacity of sEH deficiency and inhibition to regulate ER stress response (Bettaieb et al, 2013), the effects of sEH pharmacological inhibition on ER stress in control and sEHI-treated mice were determined. We evaluated activation of ER transmembrane proteins protein kinase R-like ERregulated kinase (PERK) and IRE1a, and their downstream targets a-subunit of eukaryotic translation initiation factor 2 (eIF2a) and XBP1, respectively (Ron and Walter, 2007;Hotamisligil, 2010).…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, sEH is a physiological regulator of endoplasmic reticulum (ER) stress. sEH inhibition attenuates high-fat diet-induced ER stress in vivo and chemical-induced ER stress in cultured cells (Bettaieb et al, 2013). Activation of ER stress is associated with AP (Kubisch et al, 2006), and treatment with ER chaperones mitigates the disease in animal models (Seyhun et al, 2011;Malo et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Soluble Epoxide Hydrolase Pharmacological Inhibition Ameliorates Experimental Acute Pancreatitis in Mice

et al. 2015

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Acute pancreatitis (AP) is an inflammatory disease, and is one of the most common gastrointestinal disorders worldwide. Soluble epoxide hydrolase (sEH; encoded by Ephx2) deficiency and pharmacological inhibition have beneficial effects in inflammatory diseases. Ephx2 whole-body deficiency mitigates experimental AP in mice, but the suitability of sEH pharmacological inhibition for treating AP remains to be determined. We investigated the effects of sEH pharmacological inhibition on cerulein-and arginine-induced AP using the selective sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), which was administered before and after induction of pancreatitis. Serum amylase and lipase levels were lower in TPPU-treated mice compared with controls. In addition, circulating levels and pancreatic mRNA of the inflammatory cytokines tumor necrosis factor-a, interleukin Il-1b, and Il-6 were reduced in TPPU-treated mice. Moreover, sEH pharmacological inhibition before and after induction of pancreatitis was associated with decreased cerulein-and arginine-induced nuclear factor-kB inflammatory response, endoplasmic reticulum stress, and cell death. sEH pharmacological inhibition before and after induction of pancreatitis mitigated cerulein-and arginineinduced AP. This work suggests that sEH pharmacological inhibition may be of therapeutic value in acute pancreatitis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Soluble Epoxide Hydrolase Pharmacological Inhibition Ameliorates Experimental Acute Pancreatitis in Mice

et al. 2015

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“…CYP-derived EETs are key regulators of a myriad of biological processes in the cardiovascular system, including vascular tone and infl ammation ( 7,8 ). It also has been reported that EETs elicit protective effects in obesity-associated metabolic disease (9)(10)(11)(12). However, the impact of adipogenesis and obesity on EET biosynthesis in adipose tissue and the functional role of EETs in the regulation of adipogenesis and the pathogenesis of obesity remains poorly understood.…”

Section: Eicosanoid Extraction and Measurementsmentioning

confidence: 99%

Functional characterization of cytochrome P450-derived epoxyeicosatrienoic acids in adipogenesis and obesity

Zha

Edin

Vendrov

et al. 2014

Journal of Lipid Research

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Obesity is a major public health problem that contributes to the development of type 2 diabetes and cardiovascular disease ( 1 ). Excessive lipid accumulation in adipose tissue is a key pathological driver of obesity, and is manifested by an increase in the number (hyperplasia) and size (hypertrophy) of adipocytes. Differentiation of preadipocytes to mature adipocytes (adipogenesis) is an integral mediator of this process, and is under the control of a transcription factor network that regulates lipid biosynthesis and metabolism ( 2 ). Most notably, PPAR-␥ , CCAAT/ enhancer-binding protein (C/EBP) ␣ , and sterol regulatoryelement-binding protein (SREBP)1c are central mediators of this process through the regulation of LPL, acetyl-CoA carboxylase 1 (ACC1), and FAS expression ( 2, 3 ). Sustained activation of this process, however, is a key pathological driver of obesity that results in adipocyte dysfunction, glucose intolerance, and ultimately the development of insulin resistance and type 2 diabetes ( 4, 5 ). Consequently, an improved understanding of the key pathways that regulate adipogenesis and adipocyte function offers enormous potential to facilitate the development of novel therapeutic strategies that mitigate the development and progression of obesity-associated metabolic diseases. Abstract

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“…A significant decrease in number of ulcers in murine intestine associated with a lower level of TNF-a in serum was also observed. Though the role of sEHI in minimizing NSAID-induced ulceration through TNF-a/NF-kB is established, its effect on other downstream regulators such as JNK and caspase 3 cannot be ruled out, because sEH inhibition in HepG2 cells and adipocytes decreases activation of JNK, caspase 3, p38, and cell death at least in part by decreasing ER stress (Bettaieb et al, 2013). Certain types of white blood cell also contribute to ulcer formation through production of cytokines such as TNF-a.…”

Section: Discussionmentioning

confidence: 99%

Anti-Ulcer Efficacy of Soluble Epoxide Hydrolase Inhibitor TPPU on Diclofenac-Induced Intestinal Ulcers

Goswami

Wan

Yang

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Proton pump inhibitors such as omeprazole (OME) reduce the severity of gastrointestinal (GI) ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs) but can also increase the chance of dysbiosis. The aim of this study was to test the hypothesis that preventive use of a soluble epoxide hydrolase inhibitor (sEHI) such as TPPU can decrease NSAID-induced ulcers by increasing anti-inflammatory epoxyeicosatrienoic acids (EETs). Dose-[10, 30, and 100 mg/kg, by mouth (PO)] and time-dependent (6 and 18 hours) ulcerative effects of diclofenac sodium (DCF, an NSAID) were studied in the small intestine of Swiss Webster mice. Dose-dependent effects of TPPU (0.001-0.1 mg/kg per day for 7 days, in drinking water) were evaluated in DCF-induced intestinal toxicity and compared with OME (20 mg/kg, PO). In addition, the effect of treatment was studied on levels of Hb in blood, EETs in plasma, inflammatory markers such as myeloperoxidase (MPO) in intestinal tissue homogenates, and tissue necrosis factor-a (TNF-a) in serum. DCF dose dependently induced ulcers that were associated with both a significant (P , 0.05) loss of Hb and an increase in the level of MPO and TNF-a, with severity of ulceration highest at 18 hours. Pretreatment with TPPU dose dependently prevented ulcer formation by DCF, increased the levels of epoxy fatty acids, including EETs, and TPPU's efficacy was comparable to OME. TPPU significantly (P , 0.05) reversed the effect of DCF on the level of Hb, MPO, and TNF-a. Thus sEHI might be useful in the management of NSAID-induced ulcers.

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

Cited by 112 publications

References 66 publications

Soluble Epoxide Hydrolase Pharmacological Inhibition Ameliorates Experimental Acute Pancreatitis in Mice

Soluble Epoxide Hydrolase Pharmacological Inhibition Ameliorates Experimental Acute Pancreatitis in Mice

Functional characterization of cytochrome P450-derived epoxyeicosatrienoic acids in adipogenesis and obesity

Anti-Ulcer Efficacy of Soluble Epoxide Hydrolase Inhibitor TPPU on Diclofenac-Induced Intestinal Ulcers

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