中科院先进院:肽激素与受体GPRC6A结合,缓解NAFLD
创作:宇宙最酷Vera 审核:兵兵 03月28日
  • 用质谱鉴定出一种新的小鼠内生激素metabolitin(MTL),通过N端与受体GPRC6A紧密结合;
  • 在“肥胖-脂肪肝-II型糖尿病”小鼠模型中,腹腔注射或口服MTL均能促进葡萄糖代谢,抑制胰岛素抵抗(IR),改善脂肪性肝炎、II型糖尿病及肥胖相关表型;
  • 小肠MTL通过抑制神经降压素(NT)的分泌,激活AMPK途径,进而抑制小肠对脂质(而非胆固醇)的吸收;
  • MLT还可以促进胰高血糖素样肽段1(GLP-1)的表达;
  • MTL可作为治疗NAFLD的一个潜在药物靶点。
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兵兵
中国科学院深圳先进技术研究院任培根和JianV.Zhang团队为主导的研究成果。文章通过生物信息学的方法,筛选出一种肽激素metabolitin(MTL),发现其能够与受体GPRC6A结合,改变小鼠体内的葡萄糖和脂质代谢,进而具有缓解非酒精性脂肪性肝病(NAFLD)的潜力。
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Newly identified peptide hormone inhibits intestinal fat absorption and improves NAFLD through its receptor GPRC6A

新鉴定出肽段激素通过结合受体GPRC6A抑制肠脂肪吸收,改善非酒精性脂肪性肝病(NAFLD)

10.1016/j.jhep.2020.02.026

03-05, Article

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Background & Aims: Obesity and its related comorbidities, especially non-alcoholic fatty liver disease (NAFLD), are leading medical challenges worldwide due to various obesogenic factors in modern societies. Circulating peptides and G protein-coupled receptors (GPCRs) have gained much attention because of their biofunctions on these metabolic disorders.
Methods: In this study, based on the bioinformatics, we have identified a murine circulating pentadecapeptide flanked by potential convertase cleavage sites of osteocalcin (OCN), which we here name ‘metabolitin (MTL)’. We use ligand-receptor binding, receptor internalization, BRET and Nano ITC assays to study the binding relationship between MTL and GPRC6A. For in vivo biological studies, wild-type mice kept on a high-fat diet (HFD) were injected or gavaged with MTL to study its function on NAFLD.
Results: We have confirmed that the binding between MTL and GPRC6A, along with the interaction of GPRC6A and OCN by those in vitro biological studies. From the functional studies, both intraperitonial (i.p.) and oral administration of MTL improved NAFLD and insulin resistance (IR) potently in a mice model. Interacting with GPRC6A expressed in intestines, gavaged or i.p. injected MTL can significantly inhibit intestinal neurotensin (NT) secretion, which in turn inhibits triglyceride but not cholesterol gut absorption, mediated by AMPK pathway. In addition, GLP-1 secretion was induced by MTL treatment.
Conclusions: Overall, gavaged or i.p. injected MTL can significantly improves NAFLD symptoms through inhibiting lipid absorption and IR via reducing NT and stimulating GLP-1 secretion. MTL could be a potential therapeutic candidate for the treatment of NAFLD.

First Authors:
Bin Teng,Chen Huang

Correspondence Authors:
Jian V Zhang,Pei-Gen Ren

All Authors:
Bin Teng,Chen Huang,Chuan-Li Cheng,Anjaneyulu Udduttula,Xiang-Fang Yu,Chang Liu,Jian Li,Zhen-Yu Yao,Jing Long,Li-Fu Miao,Chao Zou,Jun Chu,Jian V Zhang,Pei-Gen Ren

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