Glutathione S-transferase Mu 2 inhibits hepatic steatosis via ASK1 suppression

Hepatic steatosis is the main characteristic of some liver metabolism diseases. However, unclear molecular mechanism of hepatic steatosis impedes the therapy of this hepatic steatosis. Glutathione-S-transferase mu 2 ( GSTM2 ), as a member of phase II drug metabolizing enzymes (DMEs), regulates cellular antioxidant and detoxificant. GSTM2 was highly up-regulated in hepatic steatosis tissues and high-fat diet (HFD) fed mice. Loss-of-function GSTM2 mouse model demonstrated that GSTM2 protected mice from excess fat accumulation. Mechanistically, GSTM2 interacted with ASK1 and suppressed its phosphorylation and the activation of subsequent downstream p38-JNK signalling. Moreover, GSTM2 overexpression in the liver effectively ameliorated hepatic lipid accumulation. Therefore, we identified GSTM2 as an important negative regulator in progression of hepatic steatosis via both its detoxification/antioxidant and inhibition of ASK1-p38/JNK signalling. This study showed potential therapeutic function of the DME in progression of hepatic steatosis. Jin et al. investigate the underlying mechanisms of hepatic steatosis and show that Glutathione-S-transferase mu 2 ( GSTM2 ), which is a drug metabolizing enzyme (DME), is upregulated in hepatic steatosis tissue from mice fed with a high fat diet. They show that GSTM2 is a negative regulator of hepatic steatosis via both detoxification/antioxidant and inhibition of ASK1-p38/JNK signalling, which sheds light on its potential as a therapeutic target.