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

Cassandra B Higgins,Brian J Debosch,Mark J Graham,Allyson L Mayer,Benjamin M Swarts,Alicyn I Stothard,Hideji Fujiwara,Yiming Zhang

doi:10.1172/jci.insight.120794

Abstract

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.

Highlights

Leveraging the generalized fasting and caloric restriction responses to mitigate metabolic disease is under intense investigation as a novel therapeutic approach against obesity, diabetes mellitus, and nonalcoholic fatty liver disease (NAFLD) [1, 2]
In light of our prior data in which we demonstrated that the autophagy complex protein ATG16L1 was required for autophagic and antisteatotic effects of trehalose in hepatocytes [9, 25], we examined whether ATG16L1 is required for Aloxe3 induction
We evaluated the effect of hepatic Aloxe3 expression in mice fed low-fat diet (LFD) or steatogenic, high trans-fat/cholesterol diet (HTFC) (12 weeks)

Summary

Introduction

Leveraging the generalized fasting and caloric restriction responses to mitigate metabolic disease is under intense investigation as a novel therapeutic approach against obesity, diabetes mellitus, and nonalcoholic fatty liver disease (NAFLD) [1, 2]. The hepatocyte is uniquely positioned at the nexus of the portal circulation — where dietary macronutrients are sensed and triaged to their metabolic fate — and the peripheral circulation, from which macronutrients are taken up and utilized or stored. Its unique anatomic positioning defines the hepatocyte’s role in coordinating the transition from fed to fasting states. The hepatocyte senses fat, protein, and carbohydrate content and rapidly alters its metabolism and its endocrine functions to coordinate peripheral responses. The therapeutic promise of caloric restriction and generalized macronutrient fasting remains limited by its clinical impracticality and unsustainability. Our laboratory and others [1, 9, 11] have examined specific pathways through which fasting and fasting-like mechanisms can be molecularly or pharmacologically leveraged to the benefit of the host

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Conclusion