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Nutrients 2018, 10(6), 679; https://doi.org/10.3390/nu10060679

IDH2 Deficiency Aggravates Fructose-Induced NAFLD by Modulating Hepatic Fatty Acid Metabolism and Activating Inflammatory Signaling in Female Mice

1
School of Human Environmental Sciences, University of Arkansas, Fayetteville, AR 72701, USA
2
Department of Food Science, Gyeongnam National University of Science and Technology, Jinju 52725, Korea
3
Department of Food and Biotechnology, Korea University, Sejong 30019, Korea
4
Poultry Science, University of Arkansas, Fayetteville, AR 72701, USA
5
Department of Pharmacology, Penn State University, Hershey, PA 17033, USA
6
School of Life Sciences and Biotechnology, BK21 Plus KNU Creative Bio-Research Group, College of Natural Sciences, Kyungpook National University, Daegu 41566, Korea
*
Authors to whom correspondence should be addressed.
Received: 18 April 2018 / Revised: 19 May 2018 / Accepted: 24 May 2018 / Published: 27 May 2018
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Abstract

Fructose is a strong risk factor for non-alcoholic fatty liver disease (NAFLD), resulting from the disruption of redox systems by excessive reactive oxygen species production in the liver cells. Of note, recent epidemiological studies indicated that women are more prone to developing metabolic syndrome in response to fructose-sweetened beverages. Hence, we examined whether disruption of the redox system through a deletion of NADPH supplying mitochondrial enzyme, NADP+-dependent isocitrate dehydrogenase (IDH2), exacerbates fructose-induced NAFLD conditions in C57BL/6 female mice. Wild-type (WT) and IDH2 knockout (KO) mice were treated with either water or 34% fructose water over six weeks. NAFLD phenotypes and key proteins and mRNAs involved in the inflammatory pathway (e.g., NF-κB p65 and IL-1β) were assessed. Hepatic lipid accumulation was significantly increased in IDH2 KO mice fed fructose compared to the WT counterpart. Neutrophil infiltration was observed only in IDH2 KO mice fed fructose. Furthermore, 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 our novel findings that IDH2 KO female mice may be more susceptible to fructose-induced NAFLD and the associated inflammatory response, suggesting a mechanistic role of IDH2 in metabolic diseases. View Full-Text
Keywords: IDH2; fructose; NAFLD; NF-κB; female mice IDH2; fructose; NAFLD; NF-κB; female mice
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Pan, J.H.; Kim, H.-S.; Beane, K.E.; Montalbano, A.M.; Lee, J.H.; Kim, Y.J.; Kim, J.H.; Kong, B.C.; Kim, S.; Park, J.-W.; Shin, E.-C.; Kim, J.K. IDH2 Deficiency Aggravates Fructose-Induced NAFLD by Modulating Hepatic Fatty Acid Metabolism and Activating Inflammatory Signaling in Female Mice. Nutrients 2018, 10, 679.

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