小柯机器人

美国马萨诸塞州总医院Russell P. Goodman研究团队发现，ChREBP被还原应激激活，并介导与GCKR相关的代谢特征。2023年12月14日，《细胞—代谢》杂志在线发表了这项成果。

研究人员表示，葡萄糖激酶调节因子（GCKR）编码肝脏葡萄糖激酶（GCK）调节因子 GKRP，在全基因组关联研究（GWAS）中，GCKR 的常见遗传变异影响多种代谢特征，使 GCKR 成为基因组中最具多向性的GWAS基因位点之一。目前尚不清楚其原因。之前的研究表明，GCKR会影响肝脏细胞膜NADH/NAD⁺比率，也称为还原压力。

研究人员证明还原压力足以激活转录因子ChREBP，并且是GKRP-GCK相互作用、葡萄糖和乙醇激活ChREBP所需。研究人员表明，肝还原应激会诱导GCKR GWAS特征，如肝脂肪、循环FGF21和循环酰甘油种类的增加，这些特征也受ChREBP的影响。研究人员定义了肝还原压力的转录特征，并显示了它在脂肪肝中的上调和在人类减肥手术后的下调。这些发现凸显了 GCKR-还原压力-ChREBP轴如何影多种人体代谢特征。

附：英文原文

Title: ChREBP is activated by reductive stress and mediates GCKR-associated metabolic traits

Author: Charandeep Singh, Byungchang Jin, Nirajan Shrestha, Andrew L. Markhard, Apekshya Panda, Sarah E. Calvo, Amy Deik, Xingxiu Pan, Austin L. Zuckerman, Amel Ben Saad, Kathleen E. Corey, Julia Sjoquist, Stephanie Osganian, Roya AminiTabrizi, Eugene P. Rhee, Hardik Shah, Olga Goldberger, Alan C. Mullen, Valentin Cracan, Clary B. Clish, Vamsi K. Mootha, Russell P. Goodman

Issue&Volume: 2023-12-14

Abstract: Common genetic variants in glucokinase regulator (GCKR), which encodes GKRP, a regulator of hepatic glucokinase (GCK), influence multiplemetabolic traits in genome-wide association studies (GWASs), making GCKR one of the most pleiotropic GWAS loci in the genome. It is unclear why. Prior workhas demonstrated that GCKR influences the hepatic cytosolic NADH/NAD+ ratio, also referred to as reductive stress. Here, we demonstrate that reductivestress is sufficient to activate the transcription factor ChREBP and necessary forits activation by the GKRP-GCK interaction, glucose, and ethanol. We show that hepaticreductive stress induces GCKR GWAS traits such as increased hepatic fat, circulating FGF21, and circulating acylglycerolspecies, which are also influenced by ChREBP. We define the transcriptional signatureof hepatic reductive stress and show its upregulation in fatty liver disease and downregulationafter bariatric surgery in humans. These findings highlight how a GCKR-reductive stress-ChREBP axis influences multiple human metabolic traits.

DOI: 10.1016/j.cmet.2023.11.010

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00421-7

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
官方网址：https://www.cell.com/cell-metabolism/home
投稿链接：https://www.editorialmanager.com/cell-metabolism/default.aspx