Long-term Exercise Prevents Hepatic Steatosis: a Novel Role of FABP1 in Regulation of Autophagy-lysosomal Machinery

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent diseases worldwide. Exercise is a first-line therapy and an important preventive measure for patients with NAFLD, but the underlying mechanisms are not clear. C57BL/6 mice were fed a high-fat diet (HFD) and subjected to 12 wk swimming exercise. Exercise protected against hepatic lipid accumulation and alleviated hepatocyte damage in HFD mice. Tandem mass tag-based quantitative proteomic analyses and ingenuity pathway analysis revealed that exercise down-regulated fatty acid-binding protein (FABP)1 signaling pathway, which was most closely associated with lipid metabolism. Moreover, exercise significantly decreased FABP1 expression, and liver-specific overexpression of FABP1 abolished the protective effect of exercise in NAFLD mice. Specifically, exercise significantly increased autophagic flux restoring lysosomal function, including lysosomal proteolysis and lysosomal acidification maintenance, contributing to enhancement in autophagic clearance and subsequently alleviation of hepatic steatosis. Conversely, overexpression in the mouse liver blocked the protective effect of exercise inhibiting autophagy flux. The present study identified FABP1 inhibition-mediated replenishment of the autophagy-lysosomal machinery as a novel endogenous mechanism whereby long-term exercise improves lipid homeostasis and ameliorates hepatic steatosis in NAFLD.-Pi, H., Liu, M., Xi, Y., Chen, M., Tian, L., Xie, J., Chen, M., Wang, Z., Yang, M., Yu, Z., Zhou, Z., Gao, F. Long-term exercise prevents hepatic steatosis: a novel role of FABP1 in regulation of autophagy-lysosomal machinery.