Autophagy Regulation after Diet and Exercise in Non-alcoholic Fatty Liver Disease

Along with the rise in obesity, rates of non-alcoholic fatty liver disease (NAFLD) have also increased. NAFLD may begin with fat accumulation in the liver, but can progress to non-alcoholic steatohepatitis (NASH), fibrosis, and eventual cirrhosis. With no pharmacological treatment for NASH, lifestyle interventions appear vital to maintaining liver health. Previous work has shown aberrant mitochondrial content/quality and autophagy in models of NAFLD. Exercise is known to improve mitochondrial health and possibly autophagy, thus autophagy may be a key regulatory factor for treatment of obesity induced-NAFLD. PURPOSE: The purpose of the study was to examine how weight loss from diet or diet combined with physical activity impacts hepatic mitochondrial content, autophagy and mitochondrial autophagy (mitophagy) in NAFLD. METHODS: 48 Male C57BL/6J mice were divided into 1 of 4 groups: low fat diet (LFD, 10% fat, 18 wks), high fat diet (HFD, 60% fat diet, 18 wks.), weight loss by diet (D, 60% fat diet for 10 wks then 10% fat diet for 8 wks) or weight loss by diet and physical activity (D/PA, 60% fat diet for 10 wks, then 10% fat diet plus a running wheel for 8 wks). After interventions, livers were collected and analyzed via Western blot for markers of mitochondrial content and autophagy. Results were analyzed by one-way ANOVA with α set at 0.05. RESULTS: COX-IV and PGC-1α protein contents were approximately 50% less in HFD compared to LFD, and were restored and increased with D/PA, respectively. BNIP3 content was 45% lower in HFD compared to LFD; D/PA had 50% more BNIP3 compared to LFD controls. PINK1 content was 40% higher in D and D/PA animals compared to LFD. P-PARKIN/PARKIN levels were 40% lower in HFD, D, and D/PA compared to LFD. Whereas p-UbSer65 was 3-fold higher in HFD animals. LC3II/I ratio was 50% greater in HFD and D/PA animals, yet p62 protein content was 2.5 fold higher in HFD animals compared to LFD, D, and D/PA, with no further differences observed. CONCLUSION: High-fat diet causes disruptions in mitochondrial content, mitophagy and macroautophagy. Diet combined with physical activity are able to ameliorate these derangements