Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression.

Animals Glutathione / metabolism NF-E2-Related Factor 2 / metabolism Liver / metabolism Glutamate-Cysteine Ligase / metabolism Mice Triglycerides / metabolism Oxidative Stress Male Lipid Metabolism Mice, Knockout Mice, Inbred C57BL Oxidation-Reduction Lipogenesis / genetics

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
21 Jul 2024

Historique:

received: 19 01 2023

accepted: 12 07 2024

medline: 22 7 2024

pubmed: 22 7 2024

entrez: 21 7 2024

Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-024-50454-2 PMID: 39034312

pubmed: 39034312

doi: 10.1038/s41467-024-50454-2

pii: 10.1038/s41467-024-50454-2

doi:

Substances chimiques

Glutathione GAN16C9B8O

NF-E2-Related Factor 2 0

Glutamate-Cysteine Ligase EC 6.3.2.2

Nfe2l2 protein, mouse 0

Triglycerides 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

6152

Subventions

Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)

ID : R01CA269813, R37CA230042,

Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)

ID : R01AI150698

Informations de copyright

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