Increased Glutaminolysis Marks Active Scarring in Nonalcoholic Steatohepatitis Progression.

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.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1016/j.jcmgh.2019.12.006

Publication Info

Du, Kuo, Satish K Chitneni, Ayako Suzuki, Ying Wang, Ricardo Henao, Jeongeun Hyun, Richard T Premont, Susanna Naggie, et al. (2020). Increased Glutaminolysis Marks Active Scarring in Nonalcoholic Steatohepatitis Progression. Cellular and molecular gastroenterology and hepatology, 10(1). pp. 1–21. 10.1016/j.jcmgh.2019.12.006 Retrieved from https://hdl.handle.net/10161/26705.

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Scholars@Duke

Du

Kuo Du

Assistant Professor in Medicine
Suzuki

Ayako Suzuki

Associate Professor of Medicine
Henao

Ricardo Henao

Associate Professor in Biostatistics & Bioinformatics
Naggie

Susanna Naggie

Professor of Medicine

Dr. Susanna Naggie completed her undergraduate degrees in chemical engineering and biochemistry at the University of Maryland, College Park, and her medical education at Johns Hopkins School of Medicine. She conducted her internal medicine and infectious diseases fellowship training at Duke University Medical Center, where she also served as Chief Resident. She joined the faculty in the Duke School of Medicine in 2009. She is a Professor of Medicine and currently holds appointments at the Duke University School of Medicine, at the Duke Clinical Research Institute, and at the Durham Veterans Affairs Medical Center. Dr. Naggie is a clinical investigator with a focus in clinical trials in infectious diseases and translational research in HIV and liver disease. She is a standing member of the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents and the CDC/NIH/IDSA-HIVMA Opportunistic Infections Guideline. She is the Vice Dean for Clinical and Translational Research and Director for the Duke Clinical and Translational Sciences Institute.

Moylan

Cynthia Ann Moylan

Associate Professor of Medicine

My research interests focus on the study of chronic liver disease and primary liver cancer, particularly from metabolic dysfunction associated steatotic liver disease (MASLD), formerly called nonalcoholic fatty liver disease (NAFLD).  As part of the MASLD Research Team at Duke, we are investigating the role of environmental contaminants, epigenetics, and genetics on the development of advanced fibrosis and liver cancer from MASLD and other chronic liver diseases.  We are also interested in understanding risks for progressive liver disease including developmental programming and in utero exposures and have been investigating these risks through studies of the Newborn Epigenetics Study (NEST).  The long term goal of our research is to develop non-invasive biomarkers to identify those patients at increased risk for cirrhosis and end stage liver disease in order to risk stratify patients as well as to develop better preventative and therapeutic strategies.

Bashir

Mustafa Shadi Rifaat Bashir

Professor of Radiology

Hepatobiliary and pancreatic imaging
Liver cancer (hepatocellular carcinoma)
Fatty liver, NAFLD, and NASH
Chronic liver disease and cirrhosis
Pancreatic cancer
Technical development in MRI
Quantitative imaging

Diehl

Anna Mae Diehl

Florence McAlister Distinguished Professor of Medicine

Our lab has a long standing interest in liver injury and repair. To learn more about the mechanisms that regulate this process, we study cultured cells, animal models of acute and chronic liver damage and samples from patients with various types of liver disease. Our group also conducts clinical trials in patients with chronic liver disease. We are particularly interested in fatty liver diseases, such as alcoholic fatty liver disease and nonalcoholic fatty liver disease (NAFLD).

Research by our group has advanced understanding in two main areas: 1) immune system regulation of liver injury and regeneration and 2)the role of fetal morphogens, such as the hedgehog pathway, in regulating fibrotic responses to liver damage. Our basic research programs have been enjoyed continuous NIH support since 1989. We welcome students, post-doctoral fellows and visiting scientists who have interests in this research area to contact us about training opportunities and potential collaborations.

Since 2001 we have also been an active participant in the NIDDK-funded Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN), a national consortium comprised of 8 university medical centers selected to generate a national registry for patients with NAFLD and to conduct multicenter treatment trials for this disorder. We are actively recruiting patients for this program, as well as a number of other industry-supported NAFLD studies.


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