Regulatory lipid vicinal diols counteract the biological activity of epoxy fatty acids and can act as biomarkers and mechanisms for disease progression

Polyunsaturated fatty acids (PUFAs) are essential fatty acids required for human health and are obtained primarily from food or synthesized in the body by highly regulated processes. The metabolites of these lipids, formed largely through the action of cyclooxygenase, lipoxygenase, or cytochrome P450 (CYP450) enzymes, are responsible for multiple biological functions including inflammation, tissue repair, cell proliferation, blood vessel permeability, and immune cell behavior. The role of these regulatory lipids in disease has been well studied since their discovery as druggable targets; however, the metabolites generated downstream of these pathways have only recently gained attention for regulating biology. Specifically, the biological activity of lipid vicinal diols formed from the metabolism of CYP450-generated epoxy fatty acids (EpFA) by epoxide hydrolases were previously thought to have little biological activity but increasingly are recognized as promoting inflammation and brown fat adipogenesis, and exciting neurons through the regulation of ion channel activity at low concentrations. These metabolites also appear to balance the action of the EpFA precursor. For example, EpFA demonstrate the ability to resolve inflammation and reduce pain, while some lipid diols, through opposing mechanisms, promote inflammation and pain. This review describes recent studies that highlight the role of regulatory lipids, focusing on the balance between EpFA and their diol metabolites in promoting or resolving disease.