Nature:胰高血糖素刺激肝脏糖异生作用
创作:兵兵 审核:兵兵 03月28日
  • 文章结合体内外实验结果发现,胰高血糖素通过增加肝脏甘油三酯脂肪酶活性、肝内脂解、肝脏内乙酰辅酶A浓度、丙酮酸羧化酶通量以及线粒体内脂质氧化刺激肝脏糖异生;
  • 在大鼠和小鼠模型中,血浆胰高血糖素浓度的升高,促进肝脏线粒体对脂质的氧化代谢,进而缓解高脂膳食诱导的肝脏脂肪变性和胰岛素抗性;
  • 对线粒体内脂质氧化刺激由1型三磷酸肌醇受体(INSP3R1)所介导,敲除该基因后,胰高血糖素对肝脏糖脂代谢的这种刺激作用也消失。
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兵兵
耶鲁大学内分泌学家Gerald Shulman教授发表在《Nature》上的文章。基于二型糖尿病和非酒精性脂肪肝在分子机制上的相似性,研究从胰高血糖素入手,发现胰高血糖素除了引起肝糖异生,还有促进肝内脂肪分解的作用。并且,肝脏内脂质在线粒体的氧化代谢是由INSP3R1所介导。研究又通过基因敲除和慢性药物干预实验对该结果进行验证。INSP3R1介导的线粒体钙转运过程或是发挥该作用的关键靶点。该研究为2型糖尿病和非酒精性脂肪性肝病的治疗提供了新靶点。
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Nature [IF:42.778]

Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis

胰高血糖素通过INSP3R1介导的肝脏脂解刺激葡萄糖异生作用

10.1038/s41586-020-2074-6

03-04, Article

Abstract & Authors:展开

Abstract:收起
Although it is well-established that reductions in the ratio of insulin to glucagon in the portal vein have a major role in the dysregulation of hepatic glucose metabolism in type-2 diabetes1,2,3, the mechanisms by which glucagon affects hepatic glucose production and mitochondrial oxidation are poorly understood. Here we show that glucagon stimulates hepatic gluconeogenesis by increasing the activity of hepatic adipose triglyceride lipase, intrahepatic lipolysis, hepatic acetyl-CoA content and pyruvate carboxylase flux, while also increasing mitochondrial fat oxidation—all of which are mediated by stimulation of the inositol triphosphate receptor 1 (INSP3R1). In rats and mice, chronic physiological increases in plasma glucagon concentrations increased mitochondrial oxidation of fat in the liver and reversed diet-induced hepatic steatosis and insulin resistance. However, these effects of chronic glucagon treatment—reversing hepatic steatosis and glucose intolerance—were abrogated in Insp3r1 (also known as Itpr1)-knockout mice. These results provide insights into glucagon biology and suggest that INSP3R1 may represent a target for therapies that aim to reverse nonalcoholic fatty liver disease and type-2 diabetes.

First Authors:
Rachel J Perry

Correspondence Authors:
Gerald I Shulman

All Authors:
Rachel J Perry,Dongyan Zhang,Mateus T Guerra,Allison L Brill,Leigh Goedeke,Ali R Nasiri,Aviva Rabin-Court,Yongliang Wang,Liang Peng,Sylvie Dufour,Ye Zhang,Xian-Man Zhang,Gina M Butrico,Keshia Toussaint,Yuichi Nozaki,Gary W Cline,Kitt Falk Petersen,Michael H Nathanson,Barbara E Ehrlich,Gerald I Shulman

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