진병창 (MGH/Harvard Medical School) | 한빛사논문 > 한빛사

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조회714

MGH/Harvard Medical School

Cell Metab., December 14 | https://doi.org/10.1016/j.cmet.2023.11.010 ChREBP is activated by reductive stress and mediates GCKR-associated metabolic traits

Charandeep Singh,^1,2,13 Byungchang Jin,^1,2,13 Nirajan Shrestha,^1,2 Andrew L. Markhard,³ Apekshya Panda,^3,4,5 Sarah E. Calvo,^3,4,5 Amy Deik,⁴ Xingxiu Pan,⁶ Austin L. Zuckerman,^6,7,8 Amel Ben Saad,⁹ Kathleen E. Corey,¹ Julia Sjoquist,¹ Stephanie Osganian,¹ Roya AminiTabrizi,¹⁰ Eugene P. Rhee,^2,11 Hardik Shah,¹⁰ Olga Goldberger,³ Alan C. Mullen,⁹ Valentin Cracan,^6,12 Clary B. Clish,⁴ Vamsi K. Mootha,^3,4,5 and Russell P. Goodman ^1,2,14,*

¹Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA

²Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA

³Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA

⁴Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA

⁵Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA

⁶The Scintillon Institute, San Diego, CA 92121, USA

⁷Program in Mathematics and Science Education, University of California, San Diego, La Jolla, CA 92093

⁸Program in Mathematics and Science Education, San Diego State University, San Diego, CA 92120

⁹Division of Gastroenterology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA

¹⁰Metabolomics Platform, Comprehensive Cancer Center, the University of Chicago, Chicago, IL 60637, USA

¹¹Nephrology Division, Massachusetts General Hospital, Boston, MA 02114, USA

¹²Department of Chemistry, the Scripps Research Institute, La Jolla, CA 92037, USA

¹³These authors contributed equally

¹⁴Lead contact

^*Corresponding author: correspondence to Russell P. Goodman

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.

논문정보

형식Research article
게재일2023년 12월 (BRIC 등록일 2023-12-18)
연구진국외 연구진
분야 의약학 > 분자세포의학

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