Research Center for Reproduction and Health Development, Institute of Biomedicine and biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China 518055; Shenzhen College of Advanced Technology, University of Chinese Academy of Sciences, Shenzhen, Guangdong, China, 518055.
Research Center for Reproduction and Health Development, Institute of Biomedicine and biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China 518055.
J Hepatol. 2020 Aug;73(2):383-393. doi: 10.1016/j.jhep.2020.02.026. Epub 2020 Mar 6.
BACKGROUND & AIMS: Circulating peptides and G protein-coupled receptors (GPCRs) have gained much attention because of their biofunctions in metabolic disorders including obesity and non-alcoholic fatty liver disease (NAFLD). Herein, we aimed to characterize the role and therapeutic potential of a newly identified peptide hormone in NAFLD.
Using bioinformatics, we identified a murine circulating pentadecapeptide flanked by potential convertase cleavage sites of osteocalcin (OCN), which we named 'metabolitin (MTL)'. We used ligand-receptor binding, receptor internalization, bioluminescence resonance energy transfer and Nano isothermal titration calorimetry 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 in NAFLD.
We confirmed that MTL binds to GPRC6A and OCN interacts with GPRC6A using in vitro biological studies. Both intraperitoneal and oral administration of MTL greatly improved NAFLD and insulin resistance in a mouse model. Interacting with GPRC6A expressed in intestines, MTL can significantly inhibit intestinal neurotensin secretion, which in turn inhibits triglyceride but not cholesterol gut absorption, mediated by the 5'AMP-activated protein kinase pathway. In addition, glucagon like peptide-1 secretion was induced by MTL treatment.
Oral or intraperitoneal MTL significantly improves the symptoms of NAFLD by inhibiting lipid absorption and insulin resistance. MTL could be a potential therapeutic candidate for the treatment of NAFLD.
A novel murine peptide hormone, herein named 'metabolitin', inhibits fatty acid absorption and improves systemic insulin resistance in a murine model of obesity and non-alcoholic fatty liver disease. Thus, metabolitin has therapeutic potential for the treatment of patients with non-alcoholic fatty liver disease.
循环肽和 G 蛋白偶联受体（GPCR）因其在代谢紊乱中的生物功能而备受关注，包括肥胖和非酒精性脂肪性肝病（NAFLD）。在此，我们旨在研究一种新鉴定的肽激素在 NAFLD 中的作用和治疗潜力。
使用生物信息学，我们鉴定了一种被骨钙素（OCN）潜在转换酶切割位点包围的鼠循环十五肽，我们将其命名为“代谢素（MTL）”。我们使用配体-受体结合、受体内化、生物发光共振能量转移和纳米等温滴定量热法测定来研究 MTL 与 GPRC6A 之间的结合关系。对于体内生物学研究，将高脂饮食（HFD）喂养的野生型小鼠注射或灌胃 MTL，以研究其在 NAFLD 中的功能。
我们通过体外生物学研究证实了 MTL 与 GPRC6A 结合，OCN 与 GPRC6A 相互作用。MTL 腹腔内和口服给药均可显著改善 NAFLD 和胰岛素抵抗的小鼠模型。与肠道中表达的 GPRC6A 相互作用，MTL 可显著抑制神经降压素的分泌，进而通过 5'AMP 激活蛋白激酶途径抑制甘油三酯而非胆固醇的肠道吸收。此外，MTL 处理可诱导胰高血糖素样肽-1 的分泌。
口服或腹腔内 MTL 通过抑制脂质吸收和胰岛素抵抗显著改善 NAFLD 症状。MTL 可能是治疗 NAFLD 的潜在治疗候选物。
一种新型鼠肽激素，本文命名为“代谢素”，可抑制肥胖和非酒精性脂肪性肝病小鼠模型中脂肪酸的吸收并改善全身胰岛素抵抗。因此，代谢素对治疗非酒精性脂肪性肝病患者具有治疗潜力。
