G蛋白偶联受体GPR110作为肥胖相关并发症新治疗靶点的机制研究

Obesity is a risk factor for numerous comorbidities, including type 2 diabetes, cardiovascular diseases and certain types of cancers, and imposes a huge healthcare burden on our society. It is therefore of great importance to study the pathophysiological mechanisms involved in the development of obesity-related metabolic complications and to explore new cost-effective therapies for these diseases. In this study, we will investigate the biological significance and molecular mechanism of an orphan GPCR - GPR110 in hepatic lipid uptake and glucose metabolism by both molecular and physiological approaches. First, we will use both a gain-of-function and a loss-of-function approach in a diet-induced obese mouse model to comprehensively evaluate the effects of hepatic GPR110 on glucose and lipid metabolism. Second, we will define the mechanism of GPR110 in regulating energy homeostasis in both physiological and pathological stages. Finally, the potential of using artificial ligands to regulate GPR110 activity will be explored. Our findings will not only explore the function of GPR110 in energy metabolism. As the amino acid sequence and expression pattern of GPR110 are highly conserved from mouse to human, findings from this study will also provide valuable information for the development of new therapeutic strategies for metabolic diseases.

随着我国经济的快速发展、饮食结构和环境因素的改变，肥胖人群急剧增加。肥胖是多种疾病的风险因素，如2型糖尿病、脂肪肝、心血管疾病以及某些癌症。因此，研究并揭示引发肥胖相关代谢并发症的病生理机制以及探索对抗这种全球性流行病的新靶点、研发更为安全有效的药物迫在眉睫且具有重要意义。本课题组长期专注于代谢性疾病和新型代谢药物的基础研究。本项目将旨在探索一种新的孤儿G 蛋白偶联受体 GPR110在代谢失调中所扮演的重要角色和作为治疗靶点的可能性。

近期研究表明G蛋白偶联受体110（GPR110）是一种致癌基因，该结论主要基于GPR110在许多癌症类型中的高表达；且敲除GPR110后可以减少细胞的迁移、入侵和增殖。然而，正常情况下GPR110主要在健康人的肝脏中表达，但其在肝脏中的功能还没有被发现。而肝脏GPR110的表达水平在肥胖者中急剧下降。在此，我们研究了GPR110在肝脏代谢中的作用。通过重组腺相关病毒介导的基因递送系统和反义寡核苷酸来调控饮食诱导的肥胖小鼠的肝脏GPR110表达水平，研究GPR110在肝脏脂肪变性中的作用。利用转录组分析和不同程度的非酒精性脂肪肝（NAFLD）患者的肝脏组织存档活检标本，研究其临床意义。肝脏中GPR110的表达与肥胖小鼠和非酒精性脂肪肝患者肝脏中的脂肪含量直接相关。通过RNA测序分析，发现硬脂酰辅酶1（SCD1）是肝脏新脂肪生成的关键酶，是GPR110的下游目标。后续通过利用肝脏特异性SCD1抑制剂MK8245和原代肝细胞中针对SCD1的特异性shRNAs治疗，分别改善了GPR110高表达小鼠的肝脏脂肪变性和肝细胞的脂质状况。上述实验结果表明GPR110通过控制SCD1的表达来调节肝脏脂质代谢。GPR110表达的下调有可能作为一种保护机制，阻止肥胖者肝脏中脂肪的过度积累。我们的研究结果不仅揭示了NALFD进展的新机制，而且还提出了可以通过靶向GPR110来对抗NAFLD的新型治疗方法。