细胞因子GDF15在非酒精性脂肪性肝炎中的作用及机理研究

非酒精性脂肪性肝炎（NASH）是非酒精性脂肪肝中的一种严重形式，可导致肝硬化和肝癌，但尚无针对NASH的直接治疗药物。Kupffer细胞（KC）活化是NASH发生发展的关键机制，然而如何抑制KC活化未明。我们初步研究发现，细胞因子GDF15在NASH患者血清及小鼠的肝细胞中均显著升高。在诱导NASH的过程中，GDF15蛋白干预的小鼠NASH症状和小叶炎症明显较轻；GDF15受体GFRAL在肝脏中选择性在KC表达。因此我们推测GDF15作为肝细胞因子以旁分泌的形式作用于KC，通过GFRAL抑制KC活化从而限制NASH进展。本项目将采用两种小鼠NASH模型来明确GDF15在治疗NASH中的作用，并通过KC特异性GFRAL敲除小鼠，深入研究GDF15是否通过调控KC而影响NASH发展并揭示潜在分子机制。这些发现将加深我们对KC在NASH中功能和对KC调控的认识，并为开发NASH药物靶点提供依据。

Nonalcoholic steatohepatitis (NASH) is the severe form of nonalcoholic fatty liver diseases which has the high potential to progress to cirrhosis and hepatocellular carcinoma. However, there are currently no approved therapy for direct treatment of NASH. Activation of Kupffer cells is of critical importance in the development of NASH. However, how to inhibit Kupffer cell activation remains poorly understood. Growth differentiation factor 15 (GDF15) is a cytokine originally isolated from activated human macrophages. Our pilot study demonstrated a drastic increase in both serum level and hepatic expression of GDF15 in NASH patients and mice with diet-induced NASH, respectively. Serum GDF15 level was closely associated with lobular inflammation. We then administered mice with simple steatosis with recombinant GDF15 and found that the GDF15-treated mice were resistant to further development of NASH as compared to the control group receiving PBS. By further unbiased screening of mouse liver cells using flow cytometry, we observed selective expression of GFRAL, the specific receptor for GDF15, in Kupffer cells. Thus, we propose that GDF15, as a hepatokine, acts on Kupffer cells in a paracrine manner to inhibit Kupffer cell activation through GFRAL, thereby protecting against NASH. To test this hypothesis, we will use two mouse models of NASH combined with pair-feeding experiments to further clarify the pharmacological effects of GDF15 on treatment of NASH. We will also investigate whether GDF15 alleviates NASH through its actions on Kupffer cells and the underlying signalling pathways by using Kupffer cell-selective GFRAL knockout mice and ex-vivo culture of Kupffer cells. Findings from this study will provide scientific basis for future development of novel therapeutics targeting GDF15-GFRAL axis to prevent and/or treat NASH clinically.