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Abstract
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.
Highlights
IntroductionWhite adipose tissue (WAT) contributes to systemic metabolic flexibility by efficiently storing surplus fuel in the form of triglycerides (TGs) and by quickly mobilizing fatty acids (FAs) to supply peripheral organs to meet their energetic demands
Animals fed a 30-week Western-style diet (WD) (WD30) gained significantly more weight (p < 0.01). Their absolute and relative liver weights and the amount of epididymal fat were increased compared to mice fed the control diet for 30 weeks (CD30) (p < 0.01) (Table 1)
Extending the period of WD feeding from 24 weeks to 30 resulted in the induction of a more advanced stage of nonalcoholic fatty liver disease (NAFLD) in C57BL/6J mice
Summary
White adipose tissue (WAT) contributes to systemic metabolic flexibility by efficiently storing surplus fuel in the form of triglycerides (TGs) and by quickly mobilizing fatty acids (FAs) to supply peripheral organs to meet their energetic demands. These processes are coordinated via endocrine cues and metabolic signals [1]. WAT is highly integrated with other tissues, especially the liver [1]. The liver is a major metabolic organ that coordinates the metabolic flexibility of the whole body, with hepatocyte mitochondria being key partners in fine-tuning this process [3]
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