Increased Glutaminolysis Marks Active Scarring in Nonalcoholic Steatohepatitis Progression

Kuo Du, Satish K. Chitneni, Ayako Suzuki, Ying Wang, Ricardo Henao, Jeongeun Hyun, Richard T. Premont, Susanna Naggie, Cynthia A. Moylan, Mustafa R. Bashir, Manal F. Abdelmalek, Anna Mae Diehl

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

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.
Original languageEnglish (US)
Pages (from-to)1-21
Number of pages21
JournalCellular and Molecular Gastroenterology and Hepatology
Volume10
Issue number1
DOIs
StatePublished - Jan 1 2020
Externally publishedYes

Bibliographical note

Generated from Scopus record by KAUST IRTS on 2023-02-15

ASJC Scopus subject areas

  • Gastroenterology
  • Hepatology

Fingerprint

Dive into the research topics of 'Increased Glutaminolysis Marks Active Scarring in Nonalcoholic Steatohepatitis Progression'. Together they form a unique fingerprint.

Cite this