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Serine synthesis via reversed SHMT2 activity drives glycine depletion and acetaminophen hepatotoxicity in MASLD.
Ghrayeb, Alia; Finney, Alexandra C; Agranovich, Bella; Peled, Daniel; Anand, Sumit Kumar; McKinney, M Peyton; Sarji, Mahasen; Yang, Dongshan; Weissman, Natan; Drucker, Shani; Fernandes, Sara Isabel; Fernández-García, Jonatan; Mahan, Kyle; Abassi, Zaid; Tan, Lin; Lorenzi, Philip L; Traylor, James; Zhang, Jifeng; Abramovich, Ifat; Chen, Y Eugene; Rom, Oren; Mor, Inbal; Gottlieb, Eyal.
Afiliación
  • Ghrayeb A; Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel.
  • Finney AC; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.
  • Agranovich B; Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel.
  • Peled D; Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel.
  • Anand SK; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.
  • McKinney MP; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.
  • Sarji M; Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel.
  • Yang D; Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA.
  • Weissman N; Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel.
  • Drucker S; Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel.
  • Fernandes SI; Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel.
  • Fernández-García J; Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel.
  • Mahan K; Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel.
  • Abassi Z; Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel.
  • Tan L; Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Lorenzi PL; Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Traylor J; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA.
  • Zhang J; Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA.
  • Abramovich I; Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel.
  • Chen YE; Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA.
  • Rom O; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular and Cellular Phys
  • Mor I; Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel. Electronic address: inbal.mor123@gmail.com.
  • Gottlieb E; Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel; Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address: egottlieb@mdanderson.org.
Cell Metab ; 36(1): 116-129.e7, 2024 01 02.
Article en En | MEDLINE | ID: mdl-38171331
ABSTRACT
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one-third of the global population. Understanding the metabolic pathways involved can provide insights into disease progression and treatment. Untargeted metabolomics of livers from mice with early-stage steatosis uncovered decreased methylated metabolites, suggesting altered one-carbon metabolism. The levels of glycine, a central component of one-carbon metabolism, were lower in mice with hepatic steatosis, consistent with clinical evidence. Stable-isotope tracing demonstrated that increased serine synthesis from glycine via reverse serine hydroxymethyltransferase (SHMT) is the underlying cause for decreased glycine in steatotic livers. Consequently, limited glycine availability in steatotic livers impaired glutathione synthesis under acetaminophen-induced oxidative stress, enhancing acute hepatotoxicity. Glycine supplementation or hepatocyte-specific ablation of the mitochondrial SHMT2 isoform in mice with hepatic steatosis mitigated acetaminophen-induced hepatotoxicity by supporting de novo glutathione synthesis. Thus, early metabolic changes in MASLD that limit glycine availability sensitize mice to xenobiotics even at the reversible stage of this disease.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hígado Graso / Enfermedad Hepática Inducida por Sustancias y Drogas Límite: Animals Idioma: En Revista: Cell Metab Asunto de la revista: METABOLISMO Año: 2024 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hígado Graso / Enfermedad Hepática Inducida por Sustancias y Drogas Límite: Animals Idioma: En Revista: Cell Metab Asunto de la revista: METABOLISMO Año: 2024 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Estados Unidos