Nonalcoholic fatty liver disease (
NAFLD) is a prevalent hepatic disease in the world. Disorders of
branched chain amino acid (BCAA) metabolism is involved in various diseases. In this study, we aim to explore the role of BCAA metabolism in the development of
NAFLD and the protective effect of BCATc Inhibitor 2, an inhibitor of cytosolic
branched chain amino acid transaminase, against
NAFLD as well as its underlying mechanism. It was found that
oleic acid induced
lipid accumulation and apoptosis in HepG2 and LO2 cells. Supplementation of BCAAs further aggravated
oleic acid-induced
lipid accumulation and apoptosis. In contrast, treatment of BCATc Inhibitor 2 ameliorated
oleic acid-induced
lipid accumulation and apoptosis. Molecularly, supplementation of BCAAs or treatment of BCATc Inhibitor 2 up-regulated or down-regulated the expression of SREBP1 and lipogenesis-related genes without affecting lipolysis-related genes. BCATc Inhibitor 2 maintained mitochondrial function by ameliorating
oleic acid-induced mitochondrial ROS generation and mitochondrial membrane potential disruption. In addition, BCATc Inhibitor 2 treatment alleviated
oleic acid-induced activation of JNK and AKT signaling pathway and Bcl2/Bax/
Caspase axis. In conclusion, our results indicate BCAA metabolism is involved in
NAFLD and BCATc Inhibitor 2 protects against
oleic acid-induced
lipid accumulation and apoptosis. These findings suggest that BCATc Inhibitor 2 is a promising candidate
drug for the treatment of
NAFLD.