The Role of Cytochrome P450 Epoxygenases, Soluble Epoxide Hydrolase, and Epoxyeicosatrienoic Acids in Metabolic Diseases

Abstract

Metabolic diseases are associated with an increased risk of developing cardiovascular disease. The features comprising metabolic diseases include obesity, insulin resistance, hyperglycemia, hyperlipidemia, and hypertension. Recent evidence has emerged showcasing a role for cytochrome P450 epoxygenases, soluble epoxide hydrolase, and epoxyeicosatrienoic acids (EETs) in the development and progression of metabolic diseases. This review discusses the current knowledge related to the modulation of cytochrome P450 epoxygenases and soluble epoxide hydrolase to alter concentrations of biologically active EETs, resulting in effects on insulin resistance, lipid metabolism, obesity, and diabetes. Future areas of research to address current deficiencies in the understanding of these enzymes and their eicosanoid metabolites in various aspects of metabolic diseases are also discussed.

Keywords: cytochrome P450 (CYP) epoxygenase; epoxyeicosatrienoic acid; insulin resistance; lipid; obesity; soluble epoxide hydrolase; type 2 diabetes.

FIGURE 1

Signaling mechanisms in glucose metabolism that protect against insulin resistance. EETs activate eNOS and insulin receptor downstream signaling pathways to promote glucose metabolism. EETs alleviate ER stress, leading to activation of adiponectin signaling, inflammation, and upregulation of adiponectin expression and signaling. EETs also reduce inflammation, leading to the activation of PI3K/AKT signaling pathways to increase glucose metabolism. Genetic disruption and/or pharmacologic inhibition of sEH increases EETs and increases islet survival and insulin secretion to promote glucose metabolism. AKT, protein kinase B; AMPK, AMP-activated protein kinase; CYP, cytochrome P450; EET, epoxyeicosatrienoic acid; eNOS, endothelial nitric oxide synthase; ER, endoplasmic reticulum; GLUT4, glucose transporter type 4; IRS-1/2, insulin receptor substrate-1/2; PI3K, phosphatidylinositol 3-kinase; sEH, soluble epoxide hydrolase.

FIGURE 2

Signaling mechanisms involved in cardiovascular complications of insulin resistance. High glucose and Ang II increase intracellular calcium, promote NF-AT into the nucleus, and enhance transcription leading to cardiac hypertrophy. CYP2J2 overexpression increases the transfer of Glut4 to the cell membrane and also activates IRS-1/PI3K/AKT eNOS and upregulates adiponectin/AMPK signaling pathways, thus reversing the process of cardiac hypertrophy. AKT, protein kinase B; AMPK, AMP-activated protein kinase; Ang II, angiotensin II; Ang II R, angiotensin II receptor; ANP, atrial natriumtic peptide; CYP2J2, cytochrome P450 2J2; EET, epoxyeicosatrienoic acid; eNOS, endothelial nitric oxide synthase; Glut4, glucose transporter type 4; IRS-1, insulin receptor substrate-1; NF-AT, nuclear factor of activated T cells; PI3K, phosphatidylinositol 3-kinase. Adapted from reference 24 with permission.