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An Advanced Murine Model for Nonalcoholic Steatohepatitis in Association with Type 2 Diabetes
Published on: April 26, 2019
Western Diet Decreases the Liver Mitochondrial Oxidative Flux of Succinate: Insight from a Murine NAFLD Model
Pavla Staňková1, Otto Kučera1, Eva Peterová1,2
1Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 500 03 Hradec Králové, Czech Republic.
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.
Insights
Mitochondrial dysfunction, specifically reduced succinate dehydrogenase activity, is key in nonalcoholic fatty liver disease (NAFLD) progression. These changes in mice on a Western diet appear adaptive, preventing overload and excessive reactive oxygen species (ROS).
Area of Science:
- Biochemistry
- Cell Biology
- Pathology
Background:
- Mitochondria are crucial in nonalcoholic fatty liver disease (NAFLD) pathogenesis.
- Succinate-activated respiration is significantly affected in mild NAFLD.
- Succinate dehydrogenase (SDH) role in NAFLD progression requires further investigation.
Purpose of the Study:
- To investigate the role of succinate dehydrogenase (SDH) in the progression of NAFLD to nonalcoholic steatohepatitis (NASH).
- To analyze mitochondrial respiration, SDH activity, gene/protein expression, hepatic succinate levels, and redox status in a mouse model of NAFLD.
Main Methods:
- C57BL/6J mice were fed a Western-style diet (WD) or control diet for 30 weeks.
- NAFLD severity was assessed histologically.
- Mitochondrial respiration, SDH activity, protein/gene expression, redox status, and metabolomics were analyzed.
Main Results:
- WD consumption reduced succinate-activated respiration and SDH activity.
- Decreased expression of sirtuin 3 (SDH activator) and SDH subunits was observed.
- Hepatic succinate levels increased, while succinate receptor 1 (SUCNR1) expression decreased.
- No significant oxidative damage was detected; changes seemed adaptive.
Conclusions:
- Reduced SDH activity and altered succinate metabolism are implicated in NAFLD/NASH progression.
- The observed mitochondrial changes may be an adaptive mechanism to prevent respiratory chain overload and ROS production.
- Targeting SDH or succinate signaling pathways could offer therapeutic strategies for NAFLD.
