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

65 Pages Posted: 25 Jul 2018 Sneak Peek Status: Review Complete

See all articles by Jorge Simon

Jorge Simon

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory

Maitane Nuñez-García

Universidad del País Vasco (UPV/EHU) - Department of Physiology

Pablo Fernández-Tussy

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory

Lucía Barbier-Torres

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory

David Fernández-Ramos

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory

Beatriz Gómez-Santos

Universidad del País Vasco (UPV/EHU) - Department of Physiology

Xabier Buqué

Universidad del País Vasco (UPV/EHU) - Department of Physiology

Fernando Lopitz-Otsoa

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory

Imanol Zubiete-Franco

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory

Virginia Gutiérrez-de Juan

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory

Diana Cabrera

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Metabolomics Platform

Cristina Alonso

Basque Government - Basque Foundation for Science (IKERBASQUE)

Paula Iruzubieta

Owl Metabolomics

Sebastiaan van Liempd

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Metabolomics Platform

Azucena Castro

Owl Metabolomics

Marta Varela-Rey

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory

Juan Manuel Falcón-Pérez

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Metabolomics Platform

Erica Villa

Università degli studi di Modena e Reggio Emilia (UNIMORE)

Javier Crespo

Research Institute Marqués de Valdecilla (IDIVAL) - Infection, Immunity and Digestive Pathology Group

Shelly C. Lu

Cedars Sinai Medical Center - Division of Digestive and Liver Diseases

Jose María Mato

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory

Patricia Aspichueta

Universidad del País Vasco (UPV/EHU) - Department of Physiology

Teresa Cardoso Delgado

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory

María Luz Martínez Chantar

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory

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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.

Suggested Citation

Simon, Jorge and Nuñez-García, Maitane and Fernández-Tussy, Pablo and Barbier-Torres, Lucía and Fernández-Ramos, David and Gómez-Santos, Beatriz and Buqué, Xabier and Lopitz-Otsoa, Fernando and Zubiete-Franco, Imanol and Gutiérrez-de Juan, Virginia and Cabrera, Diana and Alonso, Cristina and Iruzubieta, Paula and van Liempd, Sebastiaan and Castro, Azucena and Varela-Rey, Marta and Falcón-Pérez, Juan Manuel and Villa, Erica and Crespo, Javier and Lu, Shelly C. and Mato, Jose María and Aspichueta, Patricia and Delgado, Teresa Cardoso and Martínez Chantar, María Luz, Targeting Hepatic Glutaminase 1 Ameliorates Non-Alcoholic Steatohepatitis by Restoring Disrupted Hepatic Very-Low Density Lipoproteins Triglyceride Assembly (2018). Available at SSRN: https://ssrn.com/abstract=3219265 or http://dx.doi.org/10.2139/ssrn.3219265
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Jorge Simon

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory

48160 Derio, Bizkaia
Spain

Maitane Nuñez-García

Universidad del País Vasco (UPV/EHU) - Department of Physiology

Barrio Sarriena s/n
Leioa, Bizkaia 48940
Spain

Pablo Fernández-Tussy

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory

48160 Derio, Bizkaia
Spain

Lucía Barbier-Torres

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory

48160 Derio, Bizkaia
Spain

David Fernández-Ramos

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory

48160 Derio, Bizkaia
Spain

Beatriz Gómez-Santos

Universidad del País Vasco (UPV/EHU) - Department of Physiology

Barrio Sarriena s/n
Leioa, Bizkaia 48940
Spain

Xabier Buqué

Universidad del País Vasco (UPV/EHU) - Department of Physiology

Barrio Sarriena s/n
Leioa, Bizkaia 48940
Spain

Fernando Lopitz-Otsoa

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory

48160 Derio, Bizkaia
Spain

Imanol Zubiete-Franco

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory

48160 Derio, Bizkaia
Spain

Virginia Gutiérrez-de Juan

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory

48160 Derio, Bizkaia
Spain

Diana Cabrera

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Metabolomics Platform

48160 Derio, Bizkaia
Spain

Cristina Alonso

Basque Government - Basque Foundation for Science (IKERBASQUE)

Bilbao, 48011
Spain

Paula Iruzubieta

Owl Metabolomics

Parque Tecnológico de Bizkaia Edificio 502 - Plant
48610, Derio
Spain

Sebastiaan Van Liempd

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Metabolomics Platform

48160 Derio, Bizkaia
Spain

Azucena Castro

Owl Metabolomics

Parque Tecnológico de Bizkaia Edificio 502 - Plant
48610, Derio
Spain

Marta Varela-Rey

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory

48160 Derio, Bizkaia
Spain

Juan Manuel Falcón-Pérez

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Metabolomics Platform

48160 Derio, Bizkaia
Spain

Erica Villa

Università degli studi di Modena e Reggio Emilia (UNIMORE)

Viale A. Allegri 9
Modena, Modena 42121
Italy

Javier Crespo

Research Institute Marqués de Valdecilla (IDIVAL) - Infection, Immunity and Digestive Pathology Group

Edificio IDIVAL, Avenida Cardenal Herrera Oria s/n
39011 Santander, Cantabria
Spain

Shelly C. Lu

Cedars Sinai Medical Center - Division of Digestive and Liver Diseases

8700 Beverly Blvd.
Los Angeles, CA 90048
United States

Jose María Mato

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory

48160 Derio, Bizkaia
Spain

Patricia Aspichueta

Universidad del País Vasco (UPV/EHU) - Department of Physiology

Barrio Sarriena s/n
Leioa, Bizkaia 48940
Spain

Teresa Cardoso Delgado

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory

48160 Derio, Bizkaia
Spain

María Luz Martínez Chantar (Contact Author)

Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd) - Liver disease Laboratory ( email )

48160 Derio, Bizkaia
Spain

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