ALOXE3 is a hepatic fasting-responsive lipoxygenase that enhances insulin sensitivity via hepatic PPARγ

Abstract

ABSTARCTThe hepatic glucose fasting response is gaining traction as a therapeutic pathway to enhance hepatic and whole-host metabolism. However, the mechanisms underlying these metabolic effects remain unclear. Here, we demonstrate the lipoxygenase, ALOXE3, is a novel effector of the thepatic fasting response. We show that ALOXE3 is activated during fasting, glucose withdrawal, and trehalose/trehalose analogue treatment. Hepatocyte-specific ALOXE3 expression reduced weight gain and hepatic steatosis in dietaryand genetically obese (db/db) models. ALOXE3 expression moreover enhanced basal thermogenesis and abrogated insulin resistance in db/db diabetic mice. Targeted metabolomics demonstrated accumulation of the PPAR{gamma} ligand, 12-KETE in hepatocytes overexpressing ALOXE3. Strikingly, PPAR{gamma} inhibition reversed hepatic ALOXE3-mediated insulin sensitization, suppression of hepatocellular ATP production and oxygen consumption, and gene induction of PPAR{gamma} coactivator-1a (PGC1) expression. Moreover, hepatocyte-specific PPAR{gamma} deletion reversed the therapeutic effect of hepatic ALOXE3 expression on diet-induced insulin intolerance. ALOXE3 is therefore a novel effector of the hepatocellular fasting response that leverages both PPAR{gamma}-mediated and pleiotropic effects to augment hepatic and whole-host metabolism, and is thus a promising target to ameliorate metabolic disease.