Time‐of‐Day Defines the Risk of Thermally Abused Frying Oil to Renal Injury by Modulating the Diurnal Dynamics of Oxylipins

Modulation of circadian rhythms impairs homeostasis, resulting in altered susceptibility to disease development. New perspectives on nutrition emphasize the circadian timing of food intake. Here, we found that the ad libitum feeding of oxidized frying oil disrupted the conversion of epoxides to diols in the kidneys, leading to aggravated renal injury. Interestingly, the circadian rhythms of epoxides and their diols in the kidneys and plasma showed differences between the light and dark phases. We demonstrated that time-imposed feeding of fried oil during the active period resulted in limited damage to renal function, conversely, renal function was impaired during the inactive period. Remarkably, feeding with epoxy stearic acid (EpSA) from fried oil during the inactive period disrupted the rhythmicity of epoxide hydrolases and related metabolites, and fueled the progression of renal fibrosis and injury. The effect of EpSA on SMA and E-cadherin, two specific biomarkers for renal inflammation and fibrosis, are lost in knockouts of Ephx1 and Ephx2, which encodes for epoxide hydrolases. In addition, dietary supplementation with linoleic acid, which inhibits epoxide hydrolases, protected mice from damage caused by time-imposed feeding of EpSA. Our findings revealed that the time-of-day dependence of epoxide hydrolases, and circadian disruption induced by time-imposed feeding of EpSA from thermo-induced oxidized oil have adverse effects on kidney function.