Mitochondria play an essential role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Previously, we found that succinate-activated respiration was the most affected mitochondrial parameter in mice with mild NAFLD. In this study, we focused on the role of succinate dehydrogenase (SDH) in NAFLD pathogenesis. To induce the progression of NAFLD to nonalcoholic steatohepatitis (NASH), C57BL/6J mice were fed a Western-style diet (WD) or control diet for 30 weeks. NAFLD severity was evaluated histologically and the expression of selected proteins and genes was assessed. Mitochondrial respiration was measured by high-resolution respirometry. Liver redox status was assessed using glutathione, malondialdehyde, and mitochondrial production of reactive oxygen species (ROS). Metabolomic analysis was performed by GC/MS. WD consumption for 30 weeks led to reduced succinate-activated respiration. We also observed decreased SDH activity, decreased expression of the SDH activator sirtuin 3, decreased gene expression of SDH subunits, and increased levels of hepatic succinate, an important signaling molecule. Succinate receptor 1 (SUCNR1) gene and protein expression were reduced in the livers of WD-fed mice. We did not observe signs of oxidative damage compared to the control group. The changes observed in WD-fed mice appear to be adaptive to prevent mitochondrial respiratory chain overload and massive ROS production.

Department of Clinical Biochemistry and Diagnostics Charles University Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové Sokolská 581 500 05 Hradec Králové Czech Republic

Department of Medical Biochemistry Faculty of Medicine in Hradec Králové Charles University Šimkova 870 500 03 Hradec Králové Czech Republic

Department of Pathophysiology 3rd Faculty of Medicine Charles University Prague Ruská 87 100 00 Prague Czech Republic

Department of Physiology Faculty of Medicine in Hradec Králové Charles University Šimkova 870 500 03 Hradec Králové Czech Republic

The Fingerland Department of Pathology Charles University Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové Sokolská 581 500 05 Hradec Králové Czech Republic

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