G protein-coupled receptor 151 regulates glucose metabolism and hepatic gluconeogenesis.

G protein-coupled receptor 151 regulates glucose metabolism and hepatic gluconeogenesis.
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DOI:
10.1038/s41467-022-35069-9
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发表时间:
2022-12-01
影响因子:
16.6
通讯作者:
Knowles, Joshua W.
Knowles, Joshua W.
中科院分区:
综合性期刊1区
文献类型:
--
作者:
Bielczyk-Maczynska, Ewa;Zhao, Meng;Zushin, Peter-James H.;Schnurr, Theresia M.;Kim, Hyun-Jung;Li, Jiehan;Nallagatla, Pratima;Sangwung, Panjamaporn;Park, Chong Y.;Cornn, Cameron;Stahl, Andreas;Svensson, Katrin J.;Knowles, Joshua W.

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人类遗传学在识别与2型糖尿病相关的遗传变异方面发挥了重要作用。最近,在孤儿G蛋白偶联受体151(GPR151)中发现了一种罕见的假定功能丧失突变与2型糖尿病的较低比值比相关,但这种关联背后的机制仍然难以捉摸。在这里,我们表明,Gpr151是一个空腹和胰高血糖素反应的肝脏基因,调节肝脏的新生。小鼠体内Gpr151的消融导致肝细胞生成基因的抑制和响应丙酮酸的肝葡萄糖产生的减少。重要的是,Gpr151基因敲除小鼠肝脏Gpr151水平的恢复逆转了肝脏葡萄糖产生的减少。在这项工作中,我们建立了以前未知的GPR151在肝脏中的作用,为GPR151非同义突变个体的2型糖尿病风险降低提供了解释。人类G蛋白偶联受体151(GPR151)基因的罕见变异与2型糖尿病的较低比值比相关,但这种关联背后的机制仍然难以捉摸。在这里,作者表明,GPR151调节肝脏再生的过程,并影响全身葡萄糖代谢。
Human genetics has been instrumental in identification of genetic variants linked to type 2 diabetes. Recently a rare, putative loss-of-function mutation in the orphan G-protein coupled receptor 151 (GPR151) was found to be associated with lower odds ratio for type 2 diabetes, but the mechanism behind this association has remained elusive. Here we show that Gpr151 is a fasting- and glucagon-responsive hepatic gene which regulates hepatic gluconeogenesis. Gpr151 ablation in mice leads to suppression of hepatic gluconeogenesis genes and reduced hepatic glucose production in response to pyruvate. Importantly, the restoration of hepatic Gpr151 levels in the Gpr151 knockout mice reverses the reduced hepatic glucose production. In this work, we establish a previously unknown role of Gpr151 in the liver that provides an explanation to the lowered type 2 diabetes risk in individuals with nonsynonymous mutations in GPR151. Rare variants in the G-protein coupled receptor 151 (GPR151) gene in humans are associated with lower odds ratio for type 2 diabetes, but the mechanism behind this association has remained elusive. Here, the authors show that GPR151 regulates the process of hepatic gluconeogenesis and affects whole-body glucose metabolism.
分析人类敲除以验证GPR151作为减少体重指数的治疗靶标。
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