小柯机器人

胰高血糖素通过INSP3R1介导的肝脂解刺激糖异生
2020-03-07 16:24

美国耶鲁大学医学院Gerald I. Shulman小组发现,胰高血糖素通过INSP3R1介导的肝脂解刺激糖异生。2020年3月4日,《自然》在线发表了这一成果。

研究人员发现,胰高血糖素可通过增加肝脂肪甘油三酯脂肪酶、肝内脂肪分解、肝乙酰辅酶A含量和丙酮酸羧化酶通量的活性来刺激肝糖异生,同时还增加线粒体脂肪的氧化作用,所有这些都是通过刺激肌醇三磷酸受体(INSP3R1)来介导的。
 
在大鼠和小鼠中,血浆胰高血糖素浓度的长期生理增加会增加肝脏脂肪的线粒体氧化,并逆转饮食引起的肝脂肪变性和胰岛素抵抗。但是,在Insp3r1(也称为Itpr1)敲除小鼠中,慢性胰高血糖素治疗的这些作用(即逆转肝脂肪变性和葡萄糖耐受不良)消失。
 
这些结果提供了对胰高血糖素生物学的见解,并表明INSP3R1可能用于逆转非酒精性脂肪肝疾病和2型糖尿病。
 
研究人员表示,尽管公认的是,门静脉中胰岛素与胰高血糖素之比的降低在2型糖尿病的肝糖代谢失调中起主要作用,人们对胰高血糖素影响肝葡萄糖生成和代谢以及线粒体氧化机制的了解甚少。
 
附:英文原文

Title: Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis

Author: 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

Issue&Volume: 2020-03-04

Abstract: 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.

DOI: 10.1038/s41586-020-2074-6

Source: https://www.nature.com/articles/s41586-020-2074-6

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

分享到:

0