Effects of Aerobic Exercise in Hepatic Lipid Droplet-Mitochondria interaction in Non-alcoholic Fatty Liver Disease

Abstract

Lipid Droplets (LD) are highly dynamic storage organelles. In the liver, its accumulation causes non-alcoholic fatty liver (NAFL) that can progress to a more severe disease stage, nonalcoholic steatohepatitis (NASH). In hepatic and non-hepatic tissues LD interacts with mitochondria impacting lipid homeostasis. However, whether exercise modulates this interaction in the liver has not been studied yet. Our objective is to determine whether exercise modifies LD-mitochondria interaction in hepatocytes and if this interaction has an association with the severity of the disease. Two different models of NAFLD, a high fat diet (HFD) to evaluate NAFL and a methionine choline deficient diet (MCD) to evaluate NASH, were used to analyze the effects of aerobic exercise in the liver. Our results in the NAFL model showed that exercise decreased the severity of the disease and improved physical capacity compared to sedentary HFD mice. In this regard, although exercise increased the number of LD in hepatocytes, LD were smaller in size than in the sedentary HFD mice. Notably, while sedentary HFD mice increased hepatic lipid droplet (LD)-mitochondria interaction, in exercised animals, this interaction was decreased. Additionally, exercise decreased the size of the LD bound to mitochondria, and this peridroplet mitochondria (PDM) exhibited higher basal respiration and ATP synthesis capacity than PDM from sedentary HFD mice. Besides, we found a positive correlation that predicts the severity of NAFL between LD-mitochondria interaction in the liver and plasmatic ALT transaminases. This correlation is also positive between hepatic LD-mitochondria interaction and the area under the glucose tolerance test curve in this model. Our results in the NASH model resemble, to a greater extent, what we observed in the NAFL model. In NASH, exercise also reduced collagen accumulation, decreased LD-mitochondria interaction, and reduced the size of LD coupled to mitochondria compared to sedentary MCD mice. In all, our results show that aerobic exercise decreases LD-mitochondria interaction in hepatocytes and this interaction is associated with less severity of NAFL and NASH. We propose that exercise provokes an improvement of NAFLD by reduction of the hepatic LD-mitochondria interaction that in turn increase peridroplet mitochondria activity. HighlightsO_LILipid droplet (LD)-mitochondria interaction is increased in high-fat diet-induced NAFLD and choline-methionine deficient diet induced-NASH. C_LIO_LIExercise decreased LD-mitochondria interaction and is associated with reduced plasmatic ALT transaminase levels and glucose tolerance test in HFD induced-NAFLD. C_LIO_LIExercise decreases LD-mitochondria interaction, decreasing peridroplet Mitochondria (PDM) with possible lipogenic function, which induces a decrease in the LD bound to mitochondria (M-LD) in HFD-induced NAFLD. C_LIO_LIExercise decreased LD-mitochondria interaction and collagen accumulation in MCD induced-NASH. C_LI