glutaminase and Non-alcoholic-Fatty-Liver-Disease

The homeostasis of the most important nitrogen-containing intermediates, ammonia and glutamine, is a tightly regulated process in which the gut-liver axis plays a central role. Several studies revealed that nitrogen metabolism is altered in Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD), a consensus-driven novel nomenclature for Non-Alcoholic Fatty Liver Disease (NAFLD), the most common chronic liver disease worldwide. Both increased ammonia production by gut microbiota and decreased ammonia hepatic removal due to impaired hepatic urea cycle activity or disrupted glutamine synthetase activity may contribute to hepatic ammonia accumulation underlying steatosis, which can eventually progress to hyperammonemia in more advanced stages of steatohepatitis and overt liver fibrosis. Furthermore, our group recently showed that augmented hepatic ammoniagenesis

Topics: Ammonia; Glutaminase; Humans; Nitrogen; Non-alcoholic Fatty Liver Disease

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.

Topics: Animals; Fatty Acids; Glutaminase; Glutamine; Lipid Metabolism; Liver; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Proline

Nonalcoholic steatohepatitis (NASH) occurs in the context of aberrant metabolism. Glutaminolysis is required for metabolic reprograming of hepatic stellate cells (HSCs) and liver fibrogenesis in mice. However, it is unclear how changes in HSC glutamine metabolism contribute to net changes in hepatic glutaminolytic activity during fibrosis progression, or whether this could be used to track fibrogenic activity in NASH. We postulated that increased HSC glutaminolysis marks active scarring in NASH.. Glutaminolysis was assessed in mouse NASH fibrosis models and in NASH patients. Serum and liver levels of glutamine and glutamate and hepatic expression of glutamine transporter/metabolic enzymes were correlated with each other and with fibrosis severity. Glutaminolysis was disrupted in HSCs to examine if this directly influenced fibrogenesis.. The serum glutamate/glutamine ratio increased and correlated with its hepatic ratio, myofibroblast content, and fibrosis severity. Healthy livers almost exclusively expressed liver-type glutaminase (Gls2); Gls2 protein localized in zone 1 hepatocytes, whereas glutamine synthase was restricted to zone 3 hepatocytes. In fibrotic livers, Gls2 levels reduced and glutamine synthase zonality was lost, but both Slc1a5 (glutamine transporter) and kidney-type Gls1 were up-regulated; Gls1 protein was restricted to stromal cells and accumulated in fibrotic septa. Hepatocytes did not compensate for decreased Gls2 by inducing Gls1. Limiting glutamine or directly inhibiting GLS1 inhibited growth and fibrogenic activity in cultured human HSCs. Compared with healthy livers, fibrotic livers were. Glutaminolysis is a potential diagnostic marker and therapeutic target during NASH fibrosis progression.

Topics: Adult; Amino Acid Transport System ASC; Animals; Biomarkers; Cell Line; Cicatrix; Disease Models, Animal; Disease Progression; Female; Glutaminase; Glutamine; Hepatic Stellate Cells; Humans; Liver; Liver Cirrhosis; Male; Metabolomics; Mice; Middle Aged; Minor Histocompatibility Antigens; Myofibroblasts; Non-alcoholic Fatty Liver Disease; Positron-Emission Tomography

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) is overexpressed in NASH. Importantly, GLS1 inhibition reduces lipid content in choline and/or methionine deprivation-induced steatotic mouse primary hepatocytes, in human hepatocyte cell lines, and in NASH mouse livers. We suggest that under these circumstances, defective glutamine fueling of anaplerotic mitochondrial metabolism and concomitant reduction of oxidative stress promotes a reprogramming of serine metabolism, wherein serine is shifted from the generation of the antioxidant glutathione and channeled to provide one-carbon units to regenerate the methionine cycle. The restored methionine cycle can induce phosphatidylcholine synthesis from the phosphatidylethanolamine N-methyltransferase-mediated and CDP-choline pathways as well as by base-exchange reactions between phospholipids, thereby restoring hepatic phosphatidylcholine content and very-low-density lipoprotein export. Overall, we provide evidence that hepatic GLS1 targeting is a valuable therapeutic approach in NASH.

Topics: Adult; Animals; Choline; Disease Models, Animal; Female; Glutaminase; Hepatocytes; Humans; Lipid Metabolism; Lipoproteins, VLDL; Liver; Male; Methionine; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Phospholipids; Triglycerides