Dectin-1 plays a deleterious role in high fat diet-induced NAFLD of mice through enhancing macrophage activation
Dectin-1 plays a deleterious role in high fat diet-induced NAFLD of mice through enhancing macrophage activation
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DOI：
10.1038/s41401-022-00926-2
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发表时间：
2022-06
影响因子：
8.2
通讯作者：
Min-xiu Wang;Wu Luo;Lin Ye;Lei Jin;Bin Yang;Qianhui Zhang;Jianchang Qian;Yi Wang;Yi Zhang;Guang Liang
中科院分区：
文献类型：
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作者：
Min-xiu Wang;Wu Luo;Lin Ye;Lei Jin;Bin Yang;Qianhui Zhang;Jianchang Qian;Yi Wang;Yi Zhang;Guang Liang
先天免疫反应和炎症导致肝脂肪变性和非酒精性脂肪性肝病（NAFLD）。Dectin-1是天然免疫中的病原体识别受体。在这项研究中，我们研究了Dectin-1在NAFLD发病机制中的作用。我们首先发现，Dectin-1的表达在NASH患者的肝组织中显著升高。通过喂养高脂饮食（HFD）24周在小鼠中诱导NAFLD。在治疗结束时，处死小鼠，并收集其血液和肝组织用于分析。我们发现HFD喂养也增加了小鼠肝脏Dectin-1水平，与巨噬细胞浸润相关。无论是基因敲除还是联合应用Dectin-1拮抗剂海带多糖（150 mg/kg，每天两次，ip，从第16周到第24周），都能在很大程度上保护肝脏免受HFD诱导的脂质积累、纤维化和炎症反应的影响。在原代小鼠腹腔巨噬细胞（MPM）中，用棕榈酸酯（PA，200 μM）（一种在NAFLD中发现的丰富饱和脂肪酸）激发，可显著激活Dectin-1信号通路，随后转录调节促炎细胞因子的产生。Dectin-1是肝巨噬细胞活化和炎症因子诱导所必需的。由Dectin-1缺陷型巨噬细胞产生的条件培养基未能引起肝细胞脂质蓄积和肝星状细胞活化。总之，这项研究提供了主要证据，支持Dectin-1通过增强巨噬细胞促炎反应在NAFLD中发挥有害作用，并表明它可以靶向预防炎性NAFLD。
The innate immune response and inflammation contribute to hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). Dectin-1 is a pathogen recognition receptor in innate immunity. In this study, we investigated the role of Dectin-1 in the pathogenesis of NAFLD. We first showed that Dectin-1 expression was significantly elevated in liver tissues of patients with NASH. NAFLD was induced in mice by feeding high fat diet (HFD) for 24 weeks. At the end of treatment, mice were sacrificed, and their blood and liver tissues were collected for analyses. We showed HFD feeding also increased liver Dectin-1 levels in mice, associated with macrophage infiltration. Either gene knockout or co-administration of a Dectin-1 antagonist laminarin (150 mg/kg twice a day, ip, from 16thweek to 24thweek) largely protected the livers from HFD-induced lipid accumulation, fibrosis, and elaboration of inflammatory responses. In primary mouse peritoneal macrophages (MPMs), challenge with palmitate (PA, 200 μM), an abundant saturated fatty acid found in NAFLD, significantly activated Dectin-1 signaling pathway, followed by transcriptionally regulated production of pro-inflammatory cytokines. Dectin-1 was required for hepatic macrophage activation and inflammatory factor induction. Condition media generated from Dectin-1 deficient macrophages failed to cause hepatocyte lipid accumulation and hepatic stellate activation. In conclusion, this study provides the primary evidence supporting a deleterious role for Dectin-1 in NAFLD through enhancing macrophage pro-inflammatory responses and suggests that it can be targeted to prevent inflammatory NAFLD.