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Hepatocyte ALOXE3 is induced during adaptive fasting and enhances insulin sensitivity by activating hepatic PPARγ
Cassandra B. Higgins, … , Benjamin M. Swarts, Brian J. DeBosch
Cassandra B. Higgins, … , Benjamin M. Swarts, Brian J. DeBosch
Published August 23, 2018
Citation Information: JCI Insight. 2018;3(16):e120794. https://doi.org/10.1172/jci.insight.120794.
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Research Article Hepatology Metabolism

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

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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.

Authors

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

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Figure 8

Enhanced whole-body energy metabolism in db/db diabetic mice overexpressing Aloxe3.

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Enhanced whole-body energy metabolism in db/db diabetic mice overexpress...
(A) Body weight over time in db/db mice expressing empty vector or Aloxe3 in the presence or absence of GW9662. (B) Heat generation over time in db/db mice expressing GFP or Aloxe3. (C and D) Indirect calorimetric quantification of light- and dark-cycle heat generation in db/db mice expressing Aloxe3 or GFP treated with or without GW9662. (E) Fasting serum insulin determined by ELISA, serum glucose determined by colorimetric assay, and calculated HOMA-IR index based on glucose and insulin data. (F–I) Serum TG, cholesterol, LDL-C, and FFA content in db/db mice with or without hepatic Aloxe3 overexpression and with or without GW9662 treatment. Number of mice in each group is: 10, db/db AAV8GFP; 10, db/db AAV8ALOXE3; 10, AAV8ALOXE3 + GW9662. *P < 0.05, **P < 0.01, ***P < 0.001, and < 0.0001 by 2-tailed t test with Bonferroni-Dunn post hoc correction versus bracketed comparison groups.

Copyright © 2023 American Society for Clinical Investigation
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