Dissecting the NRG4 hormonal checkpoint in metabolic liver disease

内分泌激素引起的器官间串扰是哺乳动物代谢生理学的一个基本特征。激素信号的中断与胰岛素抵抗、2型糖尿病和非酒精性脂肪性肝炎(NASH)的发展有关。我们最近发现神经调节蛋白4(NRG4)是一种脂肪衍生的激素，在小鼠和人类肥胖中都会减少。利用功能获得和丧失的小鼠模型，我们证明了NRG4通过作用于肝脏来减轻肝脏脂肪生成和应激诱导的肝损伤，从而保护代谢健康。这些发现说明了NRG4在代谢信号和疾病发病机制中介导的一个新的脂肪-肝脏激素轴。肝脏的非实质细胞约占总肝细胞的30%，在组织动态平衡、肝脏代谢和疾病进展中起着重要作用。为了描述肝细胞异质性的格局和调节，我们对从健康和饮食诱导的NASH小鼠肝脏分离的NASH鼠肝细胞进行了单细胞RNA测序。这一单细胞分析揭示了对NASH发病过程中肝细胞转录重新编程的前所未有的见解。基于大量的初步数据，我们假设NRG4信号塑造了肝脏微环境，从而影响NASH及其相关肝脏疾病的进展。在这份提案中，我们计划 描述NRG4如何在单细胞分辨率下调节肝细胞的转录和功能特性。我们将确定NRG4调节肝脏免疫细胞格局的机制及其在NASH发病机制中的意义。最后，我们计划评估靶向NRG4治疗代谢性肝病的治疗潜力。

Inter-organ crosstalk via endocrine hormones is a fundamental feature of mammalian metabolic physiology. Disruptions of hormonal signaling have been linked to the development of insulin resistance, type 2 diabetes, and non-alcoholic steatohepatitis (NASH). We recently discovered Neuregulin 4 (NRG4) as a fat-derived hormone that is reduced in mouse and human obesity. Using gain- and loss-of-function mouse models, we demonstrated that NRG4 preserves metabolic health by acting on the liver to attenuate hepatic lipogenesis and stress-induced liver injury. These findings illustrate a novel adipose-hepatic hormonal axis mediated by NRG4 in metabolic signaling and disease pathogenesis. The non-parenchymal cells (NPCs) of the liver represent approximately 30% of total liver cells and play an important role in tissue homeostasis, hepatic metabolism, and disease progression. To delineate the landscape and regulation of liver cell heterogeneity, we performed single-cell RNA sequencing on NPCs isolated from healthy and diet-induced NASH mouse livers. This single-cell analysis revealed unprecedented insights into transcriptomic reprogramming of liver cells during NASH pathogenesis. Based on a body of preliminary data, we hypothesize that NRG4 signaling shapes the liver microenvironment to impinge on the progression of NASH and its associated liver disease. In this proposal, we plan to delineate how NRG4 regulates the transcriptomic and functional properties of liver cells at single-cell resolution. We will determine the mechanisms and significance of the regulation of hepatic immune cell landscape by NRG4 in mediating its effects on NASH pathogenesis. Finally, we plan to assess the therapeutic potential of targeting NRG4 for the treatment of metabolic liver disease.