Newly identified peptide hormone inhibits intestinal fat absorption and improves NAFLD through its receptor GPRC6A,Journal of Hepatology

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Newly identified peptide hormone inhibits intestinal fat absorption and improves NAFLD through its receptor GPRC6A
Journal of Hepatology ( IF 26.8 ) Pub Date : 2020-08-01 , DOI: 10.1016/j.jhep.2020.02.026
Bin Teng ₁ , Chen Huang ₂ , Chuan-Li Cheng ₃ , Anjaneyulu Udduttula ₂ , Xiang-Fang Yu ₁ , Chang Liu ₁ , Jian Li ₄ , Zhen-Yu Yao ₄ , Jing Long ₄ , Li-Fu Miao ₅ , Chao Zou ₃ , Jun Chu ₆ , Jian V Zhang ₂ , Pei-Gen Ren ₂

Affiliation

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.

中文翻译：

新鉴定的肽激素通过其受体GPRC6A抑制肠道脂肪吸收并改善NAFLD

背景和目的肥胖及其相关合并症，尤其是非酒精性脂肪性肝病 (NAFLD)，由于现代社会中的各种致肥胖因素，正在成为全球范围内的主要医学挑战。循环肽和 G 蛋白偶联受体 (GPCR) 因其对这些代谢紊乱的生物功能而备受关注。方法在这项研究中，基于生物信息学，我们确定了一种鼠循环十五肽，其两侧是骨钙素 (OCN) 的潜在转化酶切割位点，我们在此将其命名为“代谢素 (MTL)”。我们使用配体-受体结合、受体内化、BRET 和 Nano ITC 检测来研究 MTL 和 GPRC6A 之间的结合关系。对于体内生物学研究，对保持高脂肪饮食 (HFD) 的野生型小鼠注射或灌胃 MTL 以研究其对 NAFLD 的功能。结果我们通过体外生物学研究证实了MTL和GPRC6A之间的结合，以及GPRC6A和OCN的相互作用。从功能研究来看，腹膜内 (ip) 和口服 MTL 均可有效改善小鼠模型中的 NAFLD 和胰岛素抵抗 (IR)。与肠道中表达的 GPRC6A 相互作用，灌胃或腹腔注射 MTL 可以显着抑制肠道神经降压素 (NT) 分泌，从而抑制甘油三酯但不抑制胆固醇肠道吸收，由 AMPK 途径介导。此外，MTL 处理诱导 GLP-1 分泌。结论总体而言，灌胃或 ip 注射MTL可以通过减少NT和刺激GLP-1分泌来抑制脂质吸收和IR，从而显着改善NAFLD症状。MTL 可能是治疗 NAFLD 的潜在候选药物。

更新日期：2020-08-01

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