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.
Cassandra B. Higgins, Yiming Zhang, Allyson L. Mayer, Hideji Fujiwara, Alicyn I. Stothard, Mark J. Graham, Benjamin M. Swarts, Brian J. DeBosch
Submitter: Chun Liang | email@example.com
Authors: Wenhao Niu, Yihong CHEN, Zhiqing HE，Ru DING and Anna Hultgårdh-Nilsson
Department of cardiology，Shanghai Changzheng Hospital, Second Military Medical University
Published September 10, 2018
With great interest, we read the report by Higgins et al. exploring the potential role of Aloxe3 in modulation of hepatic and whole body metabolism, which could be activated by trehalose/trehalose analogue treatment,1 We raised concerns with respect to the potential risk.
Owing to beneficial effects on dehydration and protein denaturation, trehalose has been widely used in food industry, cosmetics and pharmaceuticals. But recently several epidemic outbreaks of Clostridium difficile were reported to be associated with dietary trehalose, which were confirmed to participate in the enhanced virulence, for the these strains acquired unique mechanisms to metabolize low concentrations of trehalose.2,3 Although other trehalose analogues such as lactotrehalose or galactotrehalose were investigated to exert similar metabolic modulation effects,4 such potential risk should not be underestimated and keep in mind.
Furthermore, increased level of trehalose was shown to be associated with increased risk of incident diabetes based on the data form Atherosclerosis Risk in Communities study,4 which might reflect the unignorable gap between animal model and human being. Other possible explanation of the increased trehalose detected by untargeted metabolomic profiling might be caused by passive excessive intake of processed food instead of natural ones, or reflecting the potential defected carbohydrate metabolism among the high risk population.
It indeed provides a promising target to ameliorate metabolic disease, but the potential risk should be carefully balanced and still needs furthermore studies to explore.
This work was supported by NSFC grants (91539118, 81611130092) to C.L., NSFC grants (81400336, 81770352) to R.D., CSC (201703170134) to Y.C., 17XD1405000, LJRC2015-21, and ZY 2018-2020-FWTX-1102 to C.L.
1. Higgins CB, Zhang Y, Mayer AL, et al. Hepatocyte ALOXE3 is induced during adaptive fasting and enhances insulin sensitivity by activating hepatic PPARγ. JCI Insight. 2018 Aug 23;3(16). pii: 120794.
2. Collins J, Robinson C, Danhof H, et al. Dietary trehalose enhances virulence of epidemic Clostridium difficile. Nature. 2018 Jan 18;553(7688):291-294.
3. Collins J, Danhof H, Britton RA. The role of trehalose in the global spread of epidemic Clostridium difficile. Gut Microbes. 2018 Aug 17:1-6.
4. Rebholz CM, Yu B, Zheng Z, et al. Serum metabolomic profile of incident diabetes. Diabetologia. 2018 May;61(5):1046-1054.