Targeting Hepatic Glutaminase 1 Ameliorates Non-Alcoholic Steatohepatitis by Restoring Disrupted Hepatic Very-Low Density Lipoproteins Triglyceride Assembly

Abstract

Non-Alcoholic Steatohepatitis (NASH) is characterized by the accumulation of hepatic fat in an inflammatory/fibrotic background. Herein, we show that the hepatic high-activity glutaminase 1 isoform (GLS1), the first enzyme of glutamine catabolism, is overexpressed both in clinical and pre-clinical NASH models. After methionine and choline deprivation-induced NASH, GLS1 inhibition restored hepatic phosphatidylcholine content and Very-Low Density Lipoprotein (VLDL) triglyceride export, resulting in reduced hepatic steatosis in mouse primary hepatocytes and in mouse livers. We suggest that, under these circumstances, defective glutamine fueling of anaplerotic mitochondrial metabolism and concomitant reduction of oxidative stress promotes a reprograming of serine metabolism, where serine is shifted from the generation of the antioxidant glutathione and channeled to provide one-carbon units to regenerate the methionine cycle. Restored methionine cycle induces phosphatidylcholine synthesis both from the CDP-choline and the phosphatidylethanolamine N-methyltransferase-mediated pathways. Overall, we provide evidence that hepatic GLS1 targeting is a valuable therapeutic approach in NASH.