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Megan E. Rosa1, Matthew P. Harris2, David E. Lee1, Jacob L. Brown1, Kaylee E. Poole2, Andrew Seija2, Lemuel A. Brown1, Richard A. Perry Jr.1, Tyrone A. Washington1, Joshua S. Wooten2, Nicholas P. Greene1 1University of Arkansas, 2Southern Illinois University Edwardsville; e-mail: mrosa@uark.edu

Obesity remains a key threat to public health. Along with other detriments associated with obesity, liver disease, specifically Non-Alcoholic Fatty Liver Disease (NAFLD) has dramatically increased. NAFLD may begin with fat accumulation on the liver, but can progress to steatosis, fibrosis, and eventual cirrhosis. With no pharmacological treatment for steatosis, lifestyle interventions appear to be vital to maintaining liver health. Previous work has shown aberrant mitochondrial quality and autophagy in models of fatty liver. Exercise is known to increase basal autophagy levels in muscle as well as mitochondrial health, thus autophagy may be a key regulatory factor for treatment of obesity induced-NAFLD. PURPOSE: The purpose of the study was to examine how lifestyle modifications impact hepatic autophagy and mitochondrial content in a murine model of NAFLD. METHODS: 48 C57BL/6J mice were evenly divided into one of 4 groups: low fat diet (LFD, 10% fat, 18 wks), high fat diet (HFD, 60% fat diet, 18 wks.), diet (D, 60% fat diet for 10 wks then 10% fat diet for 8 wks) or 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, animals were humanly euthanized and livers collected and snap frozen in liquid nitrogen for later analysis. Livers were homogenized and analyzed via immunoblotting for protein content of mitochondrial and autophagy related proteins. Results were analyzed via one-way analysis of variance, (ANOVA), with α set at 0.05. RESULTS: COX-IV protein content was approximately 50% less in HFD compared to LFD, and was restored to LFD levels with D/PA. PGC-1α content was 45% lower in HFD mice, D restored PGC-1α content whereas D/PA resulted in ~60% greater PGC-1α content than LFD. p62 protein content was 2.5 fold higher in HFD animals compared to LFD, D, and D/PA, with no further differences observed. BNIP3 content was 40% lower in HFD compared to LFD; D/PA had 50% more BNIP3 compared to LFD controls. CONCLUSION: Prolonged high-fat diet causes disruptions in mitochondrial content, mitophagy and macroautophagy. Combined diet and physical activity are able to restore these derangements.

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