Increased Glutaminolysis Marks Active Scarring in Nonalcoholic Steatohepatitis Progression
| Autor: | Manal F. Abdelmalek, Richard T. Premont, Jeongeun Hyun, Mustafa R. Bashir, Cynthia A. Moylan, Kuo Du, Satish K. Chitneni, Ricardo Henao, Ayako Suzuki, Ying Wang, Anna Mae Diehl, Susanna Naggie |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Liver Cirrhosis Male GLS2 liver-type glutaminase Glutamine BMI body mass index Mice 0302 clinical medicine GLS glutaminase Fibrosis Non-alcoholic Fatty Liver Disease UHPLC ultrahigh performance liquid chromatography Myofibroblasts α-KG α-ketoglutarate Original Research Chemistry Glutaminase Liver Diseases Gastroenterology Middle Aged GLS1 kidney-type glutaminase HSC hepatic stellate cell mRNA messenger RNA CT computed tomography αSMA α-smooth muscle actin HIV human immunodeficiency virus Amino Acid Liver HCV hepatitis C virus Disease Progression 030211 gastroenterology & hepatology Female Myofibroblast NASH nonalcoholic steatohepatitis IHC immunohistochemistry Adult Amino Acid Transport System ASC GS glutamine synthase IRB Institutional Review Board Stromal cell TCA tricarboxylic acid PET positron emission tomography Cell Line Minor Histocompatibility Antigens MCDE methionine/choline-deficient diet supplemented with 0.15% ethionine 03 medical and health sciences Cicatrix CDAA-HFD choline-deficient L-amino acid–defined high-fat diet medicine Hepatic Stellate Cells Animals Humans Metabolomics lcsh:RC799-869 Glutaminolysis Hepatology Metabolism Biomarker medicine.disease Disease Models Animal 030104 developmental biology MS mass spectrometry siRNA small interfering RNA Positron-Emission Tomography Hepatic stellate cell Cancer research lcsh:Diseases of the digestive system. Gastroenterology MF myofibroblast NAFLD nonalcoholic fatty liver disease Biomarkers |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Vol 10, Iss 1, Pp 1-21 (2020) |
| ISSN: | 2352-345X |
| Popis: | Background & Aims 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. Methods 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. 18F-fluoroglutamine positron emission tomography was used to determine how liver glutamine assimilation tracked with hepatic fibrogenic activity in situ. Results 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 18F-fluoroglutamine-avid by positron emission tomography, suggesting that glutamine-addicted myofibroblasts drive increased hepatic utilization of glutamine as fibrosis progresses. Conclusions Glutaminolysis is a potential diagnostic marker and therapeutic target during NASH fibrosis progression. |
| Databáze: | OpenAIRE |
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