Glutaminase 1 blockade alleviates nonalcoholic steatohepatitis via promoting proline metabolism

Nonalcoholic steatohepatitis (NASH) is emerging as a major cause of end-stage liver disease, but nowadays no pharmacological therapies are approved and there is an urgent need to develop new therapeutic targets. Glutaminase 1 (GLS1) knockdown had been put forward to alleviate NASH, but its mechanism is still unclear. Herein, to explore the exact relationship between glutamine metabolism and NASH development, we establish a NASH mice model and identified JHU-083, a proven GLS1 inhibitor, could efficiently alleviate NASH. Remarkably, JHU-083 could decrease lipid contents in the liver by enhancing fatty acid oxidation capacity considerably and transcriptomic analysis revealed JHU-083 administration could influence proline metabolism. Then we found the efficacy of JHU-083 on lipid metabolism relied on proline and when proline metabolism was blocked, GLS1 inhibitors no longer worked. Our data suggest that inhibiting glutamine hydrolysis could promote fatty acid oxidation by regulating proline metabolism, which is closely associated with NASH development and could be considered a new possible therapeutic target for NASH therapy.