ArticleNature communications2024
Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression.
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36citing papers in PubMed, 1 pooled it
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36 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Investigating the shared genetic information between serum concentration levels of liver enzymes and cholelithiasis.BMC gastroenterology · 2025Pooled it
- Brown fat protects against hepatic oxidative stress by remodeling the circulating metabolome.Cell metabolism · 2026Article
- Effects of Bound Polyphenols on Lipid Metabolism in HepG2 Cells and Glucose-InducedInternational journal of molecular sciences · 2026Article
- Glutathione Biology in Neurodegenerative and Metabolic Diseases: Molecular Mechanisms, Pathophysiological Roles, and Therapeutic Perspectives.International journal of molecular sciences · 2026Review
- Article
- Sulfur amino acid restriction prevents S-adenosylmethionine-driven liver steatosis, hepatocellular carcinoma, and metabolic remodeling in high-fat-fed GNMT-null mice.bioRxiv : the preprint server for biology · 2026Article
- The Glutamate-Glutathione axis in neuropsychiatric disorders and cancer: From shared mechanisms to non-invasive biomarkers.Redox biology · 2026Review
- Metformin Induces Ferroptosis and Inhibits Malignant Progression in Diabetic Breast Cancer.Applied biochemistry and biotechnology · 2026Article
- Substrate supply, compartmentation, and utilization in hepatic de novo lipogenesis.Trends in endocrinology and metabolism: TEM · 2026Review
- Age-related GSS promoter methylation in BMSCs drives osteoporosis and the reversal by targeted GSH delivery.Bioactive materials · 2026Article
- Inflammatory CD4iScience · 2026Article
- Hepatic glutathione depletion ameliorates MASLD through selective protein oxidation and inhibition of lipogenesis.The Journal of clinical investigation · 2026Article
- An oral immune enhancer with excellent biocompatibility for effectively strengthening body's immunity and treating cancer.Acta pharmaceutica Sinica. B · 2026Article
- Coptidis Rhizoma Alkaloids Alleviate Acetaminophen-Induced Liver Injury by Regulating GSH Metabolism and the TNF Signaling Pathway.Antioxidants (Basel, Switzerland) · 2026Article
- The road to a long lifespan in the Persian squirrel, a natural model for extended longevity: resisting free radical stress and healthy phospholipids.GeroScience · 2026Article
- Qing-Chang-Hua-Shi granule ameliorates experimental colitis by modulating Lactobacillus gasseri-mediated ferroptosis metabolic pathway.Chinese medicine · 2026Article
- Engineered Reactive Interfaces Enable Mass Spectrometry Imaging of Multiple Thiols for Decoding PFOS-Induced Redox Dysregulation.Analytical chemistry · 2026Article
- Oxidative stress and GPX2 control pancreatic vs. non-pancreatic cell fate in human endoderm.Nature communications · 2026Article
- Gastrodin improves learning and memory in sleep-deprived mice through suppression of ferroptosis in hippocampal neurons via Nrf2.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Article
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Authors and funding
38 authors.
Gloria AsantewaaDepartment of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, USA.ORCID 0000-0002-1420-4448
Emily T TuttleDepartment of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.
Nathan P WardDepartment of Metabolism and Physiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.ORCID 0000-0003-4920-0081
Yun Pyo KangDepartment of Metabolism and Physiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.ORCID 0000-0002-1149-0880
Yumi KimDepartment of Metabolism and Physiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.ORCID 0000-0001-8815-3121
Madeline E KavanaghDepartment of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA.
Nomeda GirniusDepartment of Cell Biology, Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-7267-5950
Ying ChenDepartment of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA.
Katherine RodriguezDepartment of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.
Fabio HechtDepartment of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.ORCID 0000-0001-9110-2587
Marco ZocchiDepartment of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.
Leonid Smorodintsev-SchillerDepartment of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.
TashJaé Q ScalesDepartment of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.
Kira TaylorDepartment of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.
Fatemeh AlimohammadiWilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
Renae P DuncanCenter for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.ORCID 0000-0001-6897-3755
Zachary R SechristWilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
Diana Agostini-VulajDepartment of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.ORCID 0000-0002-3847-0302
Xenia L SchaferDepartment of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, USA.
Hayley ChangDepartment of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.
Zachary R SmithDepartment of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.
Thomas N O'ConnorDepartment of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.
Sarah WhelanLeicester Cancer Research Centre, University of Leicester, Leicester, UK.
Laura M SelforsDepartment of Cell Biology, Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-1317-7353
Jett CrowdisDepartment of Cell Biology, Harvard Medical School, Boston, MA, USA.
G Kenneth GrayDepartment of Cell Biology, Harvard Medical School, Boston, MA, USA.ORCID 0000-0003-4969-670X
Roderick T BronsonDepartment of Cell Biology, Harvard Medical School, Boston, MA, USA.
Dirk BrennerExperimental and Molecular Immunology, Dept. of Infection and Immunity (DII), Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg.ORCID 0000-0001-8979-1045
Alessandro RufiniLeicester Cancer Research Centre, University of Leicester, Leicester, UK.ORCID 0000-0002-5855-655X
Robert T DirksenDepartment of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, USA.ORCID 0000-0002-3182-1755
Aram F HezelDepartment of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.
Aaron R HuberDepartment of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
Joshua MungerDepartment of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY, USA.ORCID 0000-0001-5379-9440
Benjamin F CravattDepartment of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA.ORCID 0000-0001-5330-3492
Vasilis VasiliouDepartment of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA.ORCID 0000-0003-2552-3118
Calvin L ColeWilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
Gina M DeNicolaDepartment of Metabolism and Physiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.ORCID 0000-0001-6611-6696
Isaac S HarrisDepartment of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA. isaac_harris@urmc.rochester.edu.ORCID 0000-0002-6855-2763
Funding
TRANSLATIONAL RESEARCHP30CA076292 · NCI · UNIVERSITY OF SOUTH FLORIDA · PI John L. Cleveland · 1998 to 2026
$93.5MMouse Models for Alcohol Metabolism and Tissue InjuryR24AA022057 · NIAAA · YALE UNIVERSITY · PI VASILIOU, VASILIS · 2013 to 2022
$4.5MInvestigation of NRF2-Dependent Metabolic LiabilitiesR37CA230042 · NCI · H. LEE MOFFITT CANCER CTR & RES INST · PI DENICOLA, GINA MARIE · 2018 to 2024
$2.8MPathophysiology and Treatment of Recessive RYR1 Related MyopathyR01AR078000 · NIAMS · UNIVERSITY OF ROCHESTER · PI JAMES J DOWLING, Robert T Dirksen · 2020 to 2026
$2.7MMetabolic modulation by the HCMV UL38 geneR01AI150698 · NIAID · UNIVERSITY OF ROCHESTER · PI JOSHUA C MUNGER · 2020 to 2026
$2.4MImpact of extracellular glutathione catabolism on triple-negative breast cancerR01CA269813 · NCI · UNIVERSITY OF ROCHESTER · PI Jeevisha Bajaj · 2022 to 2026
$2.2MRedox Regulation of O-GlcNAcylation Signaling in the Pathogenesis of Alcoholic Fatty Liver DiseaseR01AA028859 · NIAAA · YALE UNIVERSITY · PI Ying Chen · 2022 to 2026
$1.9MMetabolism and HCMV: determinants of the antiviral stateR01AI181865 · NIAID · UNIVERSITY OF ROCHESTER · PI JOSHUA C MUNGER · 2024 to 2026
$1.8MTraining and Research on Mechanisms of Pancreatic Cancer Associated Muscle Wasting and Related TherapiesK01CA240533 · NCI · UNIVERSITY OF ROCHESTER · PI COLE, CALVIN LLOYD · 2021 to 2025
$714kNCI NIH HHS K01 CA240533NCI NIH HHS P30 CA076292NCI NIH HHS R01 CA269813NCI NIH HHS R37 CA230042NIAAA NIH HHS R01 AA028859NIAAA NIH HHS R24 AA022057NIAID NIH HHS R01 AI150698NIAID NIH HHS R01 AI181865NIAMS NIH HHS R01 AR078000U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01CA269813, R37CA230042,U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID) R01AI150698Wellcome Trust 210890/Z/18/Z
Abstract
Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we have developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are highest in liver tissue, which is also a hub for lipid production. While the loss of GSH does not cause liver failure, it decreases lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we find that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver's balance of redox buffering and triglyceride production.
Indexed as
Glutamate-Cysteine LigaseGlutathioneLiverNF-E2-Related Factor 2TriglyceridesAnimalsLipid MetabolismLipogenesisMaleMiceMice, Inbred C57BLMice, KnockoutOxidation-ReductionOxidative StressGlutamate-Cysteine LigaseGlutathioneNfe2l2 protein, mouseNF-E2-Related Factor 2Triglycerides
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