Hepatocyte ALOXE3 is induced during adaptive fasting and enhances insulin sensitivity by activating hepatic PPARγ

JCI Insight. 2018 Aug 23;3(16):e120794. doi: 10.1172/jci.insight.120794.


The 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 epidermal-type lipoxygenase, eLOX3 (encoded by its gene, Aloxe3), is a potentially novel effector of the therapeutic fasting response. We show that Aloxe3 is activated during fasting, glucose withdrawal, or trehalose/trehalose analogue treatment. Hepatocyte-specific Aloxe3 expression reduced weight gain and hepatic steatosis in diet-induced and genetically obese (db/db) mouse models. Aloxe3 expression, moreover, enhanced basal thermogenesis and abrogated insulin resistance in db/db diabetic mice. Targeted metabolomics demonstrated accumulation of the PPARγ ligand 12-KETE in hepatocytes overexpressing Aloxe3. Strikingly, PPARγ inhibition reversed hepatic Aloxe3-mediated insulin sensitization, suppression of hepatocellular ATP production and oxygen consumption, and gene induction of PPARγ coactivator-1α (PGC1α) expression. Moreover, hepatocyte-specific PPARγ deletion reversed the therapeutic effect of hepatic Aloxe3 expression on diet-induced insulin intolerance. Aloxe3 is, therefore, a potentially novel effector of the hepatocellular fasting response that leverages both PPARγ-mediated and pleiotropic effects to augment hepatic and whole-host metabolism, and it is, thus, a promising target to ameliorate metabolic disease.

Keywords: Diabetes; Hepatology; Insulin signaling; Metabolism; Signal transduction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Fasting / physiology*
  • Hepatocytes / metabolism
  • Humans
  • Insulin / metabolism*
  • Lipoxygenase / genetics
  • Lipoxygenase / metabolism*
  • Liver / cytology
  • Liver / metabolism
  • Metabolic Syndrome / diet therapy
  • Metabolic Syndrome / etiology
  • Metabolic Syndrome / metabolism*
  • Mice
  • Mice, Transgenic
  • PPAR gamma / genetics
  • PPAR gamma / metabolism*


  • Insulin
  • PPAR gamma
  • Pparg protein, mouse
  • Lipoxygenase
  • eLOX3 protein, mouse