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

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.

• Authors: Jeong Hoon Pan, Hoe-Sung Kim, Kaleigh Elizabeth Beane, Allison Michelle Montalbano, Jin Hyup Lee, Young Jun Kim, Jun Ho Kim, Byungwhi Caleb Kong, Sangyub Kim, Jeen-Woo Park, Eui-Cheol Shin, Jae Kyeom Kim
• Journal: Nutrients (Nutrients) Vol. 10 Issue 6 (May 27 2018) ISSN: 2072-6643 [Electronic] Switzerland
• PMID: 29861476 (Publication Type: Journal Article)

Chemical References

• Cytokines
• Fatty Acids
• High Fructose Corn Syrup
• IL1B protein, mouse
• Interleukin-1beta
• Rela protein, mouse
• Transcription Factor RelA
• Fructose
• Isocitrate Dehydrogenase
• isocitrate dehydrogenase 2, mouse
• I-kappa B Kinase

Topics

• Animals
• Cytokines (blood)
• Fatty Acids (metabolism)
• Female
• Fructose (adverse effects)
• Gene Expression Regulation
• High Fructose Corn Syrup (adverse effects)
• I-kappa B Kinase (antagonists & inhibitors, genetics, metabolism)
• Interleukin-1beta (agonists, genetics, metabolism)
• Isocitrate Dehydrogenase (genetics, metabolism)
• Liver (immunology, metabolism, pathology)
• Mice, Inbred C57BL
• Mice, Knockout
• Neutrophil Infiltration
• Non-alcoholic Fatty Liver Disease (etiology, immunology, metabolism, pathology)
• Phosphorylation
• Protein Processing, Post-Translational
• Random Allocation
• Signal Transduction
• Transcription Factor RelA (genetics, metabolism)