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ChREBP is activated by reductive stress and mediates GCKR-associated metabolic traits.
Singh, Charandeep; Jin, Byungchang; Shrestha, Nirajan; Markhard, Andrew L; Panda, Apekshya; Calvo, Sarah E; Deik, Amy; Pan, Xingxiu; Zuckerman, Austin L; Ben Saad, Amel; Corey, Kathleen E; Sjoquist, Julia; Osganian, Stephanie; AminiTabrizi, Roya; Rhee, Eugene P; Shah, Hardik; Goldberger, Olga; Mullen, Alan C; Cracan, Valentin; Clish, Clary B; Mootha, Vamsi K; Goodman, Russell P.
Afiliação
  • Singh C; Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA; Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Jin B; Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA; Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Shrestha N; Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA; Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Markhard AL; Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Panda A; Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
  • Calvo SE; Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
  • Deik A; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Pan X; The Scintillon Institute, San Diego, CA 92121, USA.
  • Zuckerman AL; The Scintillon Institute, San Diego, CA 92121, USA; Program in Mathematics and Science Education, University of California, San Diego, La Jolla, CA 92093; Program in Mathematics and Science Education, San Diego State University, San Diego, CA 92120.
  • Ben Saad A; Division of Gastroenterology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
  • Corey KE; Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Sjoquist J; Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Osganian S; Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • AminiTabrizi R; Metabolomics Platform, Comprehensive Cancer Center, the University of Chicago, Chicago, IL 60637, USA.
  • Rhee EP; Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Nephrology Division, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Shah H; Metabolomics Platform, Comprehensive Cancer Center, the University of Chicago, Chicago, IL 60637, USA.
  • Goldberger O; Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Mullen AC; Division of Gastroenterology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
  • Cracan V; The Scintillon Institute, San Diego, CA 92121, USA; Department of Chemistry, the Scripps Research Institute, La Jolla, CA 92037, USA.
  • Clish CB; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Mootha VK; Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
  • Goodman RP; Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA; Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: rpgoodman@mgh.harvard.edu.
Cell Metab ; 36(1): 144-158.e7, 2024 01 02.
Article em En | MEDLINE | ID: mdl-38101397
ABSTRACT
Common genetic variants in glucokinase regulator (GCKR), which encodes GKRP, a regulator of hepatic glucokinase (GCK), influence multiple metabolic traits in genome-wide association studies (GWASs), making GCKR one of the most pleiotropic GWAS loci in the genome. It is unclear why. Prior work has demonstrated that GCKR influences the hepatic cytosolic NADH/NAD+ ratio, also referred to as reductive stress. Here, we demonstrate that reductive stress is sufficient to activate the transcription factor ChREBP and necessary for its activation by the GKRP-GCK interaction, glucose, and ethanol. We show that hepatic reductive stress induces GCKR GWAS traits such as increased hepatic fat, circulating FGF21, and circulating acylglycerol species, which are also influenced by ChREBP. We define the transcriptional signature of hepatic reductive stress and show its upregulation in fatty liver disease and downregulation after bariatric surgery in humans. These findings highlight how a GCKR-reductive stress-ChREBP axis influences multiple human metabolic traits.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Estudo de Associação Genômica Ampla / Glucoquinase Limite: Humans Idioma: En Revista: Cell Metab Assunto da revista: METABOLISMO Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Estudo de Associação Genômica Ampla / Glucoquinase Limite: Humans Idioma: En Revista: Cell Metab Assunto da revista: METABOLISMO Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos