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Prostaglandins Other Lipid Mediat. 2017 Nov;133:68-78. doi: 10.1016/j.prostaglandins.2017.08.003. Epub 2017 Aug 25.

Modulation of mitochondrial dysfunction and endoplasmic reticulum stress are key mechanisms for the wide-ranging actions of epoxy fatty acids and soluble epoxide hydrolase inhibitors.

Author information

1
Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, United States. Electronic address: abinceoglu@ucdavis.edu.
2
Department of Nutrition, The University of Tennessee, Knoxville, TN 37996-0840, United States; Graduate School of Genome Science and Technology, The University of Tennessee, Knoxville, TN 37996-0840, United States. Electronic address: abettaie@utk.edu.
3
Department of Nutrition, University of California Davis, CA 95616, United States; Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, University of California Davis, Sacramento, CA 95817, United States.
4
Department of Neurobiology, Physiology, and Behavior, University of California Davis, Davis, CA 95616, United States; Department of Physiology and Membrane Biology, University of California Davis, Davis, CA 95616, United States.
5
Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, United States.

Abstract

The arachidonic acid cascade is arguably the most widely known biologic regulatory pathway. Decades after the seminal discoveries involving its cyclooxygenase and lipoxygenase branches, studies of this cascade remain an active area of research. The third and less widely known branch, the cytochrome P450 pathway leads to highly active oxygenated lipid mediators, epoxy fatty acids (EpFAs) and hydroxyeicosatetraenoic acids (HETEs), which are of similar potency to prostanoids and leukotrienes. Unlike the COX and LOX branches, no pharmaceuticals currently are marketed targeting the P450 branch. However, data support therapeutic benefits from modulating these regulatory lipid mediators. This is being approached by stabilizing or mimicking the EpFAs or even by altering the diet. These approaches lead to predominantly beneficial effects on a wide range of apparently unrelated states resulting in an enigma of how this small group of natural chemical mediators can have such diverse effects. EpFAs are degraded by soluble epoxide hydrolase (sEH) and stabilized by inhibiting this enzyme. In this review, we focus on interconnected aspects of reported mechanisms of action of EpFAs and inhibitors of soluble epoxide hydrolase (sEHI). The sEHI and EpFAs are commonly reported to maintain homeostasis under pathological conditions while remaining neutral under normal physiological conditions. Here we provide a conceptual framework for the unique and broad range of biological activities ascribed to epoxy fatty acids. We argue that their mechanism of action pivots on their ability to prevent mitochondrial dysfunction, to reduce subsequent ROS formation and to block resulting cellular signaling cascades, primarily the endoplasmic reticulum stress. By stabilizing the mitochondrial - ROS - ER stress axis, the range of activity of EpFAs and sEHI display an overlap with the disease conditions including diabetes, fibrosis, chronic pain, cardiovascular and neurodegenerative diseases, for which the above outlined mechanisms play key roles.

KEYWORDS:

Arachidonic acid; Endoplasmic reticulum stress; Epoxy fatty acids; Epoxydocosapentaenoic acid; Mitochondria; Soluble epoxide hydrolase

[Indexed for MEDLINE]
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