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.
Highlights
Sugar-sweetened beverages, mainly consisting of high-fructose corn syrup (HFCS), are among the most popular refreshments in much of the world
It is reported that intracellular reactive oxygen species production induced by a fructose-enriched diet plays a central role in the pathogenesis of fructose-induced liver disease [3]
After 10 years of follow-up, it was recently reported that women are more susceptible to developmetabolic metabolicsyndromes syndromesinin response fructose-sweetened drink consumption
Summary
Sugar-sweetened beverages, mainly consisting of high-fructose corn syrup (HFCS), are among the most popular refreshments in much of the world. Multiple studies have identified fructose as the major culprit of many diverse metabolic syndromes including non-alcoholic fatty liver disease (NAFLD) [1]. The consumption of fructose, largely in the form of HFCS, has been found to be associated with negative metabolic outcomes such as triglyceride deposition in the liver, which is one of the hallmarks of NAFLD. Increasing evidence suggests that fructose-induced metabolic syndrome is closely associated with chronic inflammation through inflammation signaling activation in the liver [2]. It is reported that intracellular reactive oxygen species production induced by a fructose-enriched diet plays a central role in the pathogenesis of fructose-induced liver disease [3]. NADPH is critical because oxidized glutathione (i.e., endogenous cellular antioxidant) is regenerated via NADPH-consuming glutathione reductase and peroxidase systems [4]
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