IDH2 Deficiency Aggravates Fructose‐Induced NAFLD by Activating Inflammatory Signaling in Female Mice

Abstract

Fructose is a strong risk factor of non‐alcoholic fatty liver disease (NAFLD), resulting from disruption of redox systems by excessive reactive oxygen species production in the liver cells. Importantly, recent epidemiological studies indicated that women are more prone to develop metabolic syndrome in response to fructose‐sweetened beverages. Here, we examined whether disruption of redox system exacerbates fructose‐induced NAFLD conditions in female mice. The redox system was disrupted by blocking NADPH supply through mitochondrial NADP+‐dependent isocitrate dehydrogenase knock‐out (IDH2 KO) in C57BL/6 female mice. After, wild type (WT) and IDH2 KO mice were treated with either water or 34% fructose water over six weeks. NAFLD phenotypes and key proteins and mRNAs involved in inflammatory pathway (e.g., NF‐κB p65 and IL‐1β) were assessed. As results, hepatic lipid accumulation was significantly increased in IDH2 KO mice fed fructose compared to its WT counterpart. Neutrophil infiltration was observed only in IDH2 KO mice fed fructose. Further, phosphorylation of NF‐κB p65 and expression of IL‐1β was remarkably upregulated in IDH2 KO mice fed fructose, and expression of IκBα was decreased by fructose treatment in both WT and IDH2 KO groups. For the first time, we report that IDH2 KO significantly aggravates fructose‐induced NAFLD phenotypes (fatty liver and neutrophil infiltration) and related inflammatory responses (i.e., NF‐κB p65 pathway). Collectively, this study provides evidence that IDH2 deficiency may have implications on fructose‐induced NAFLD through suppression of fatty acid β‐oxidation and/or activation of the NF‐κB pathway. Given our significant phenotypes in response to fructose intervention, the present study will provide a good justification for further characterization thus warrants additional investigations to clarify mechanistic roles of mice IDH2 in metabolic diseases.Support or Funding InformationThis work was supported by the University of Arkansas, VPRED Start‐up fund (KJK, and PJH). Support has been provided in part by the Arkansas Biosciences Institute, a partnership of scientists from Arkansas Children's Hospital, Arkansas State University, the University of Arkansas‐Division of Agriculture, the University of Arkansas, Fayetteville, and the University of Arkansas for Medical Sciences. The Arkansas Biosciences Institute is the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000 (JKK, JHP, KEB, and BCK).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.