Sparcl1 promotes nonalcoholic steatohepatitis progression in mice through upregulation of CCL2
Sparcl1 promotes nonalcoholic steatohepatitis progression in mice through upregulation of CCL2
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Sparcl1 通过上调 CCL2 促进小鼠非酒精性脂肪性肝炎进展
DOI：
10.1172/jci144801
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发表时间：
2021-10-15
影响因子：
15.9
通讯作者：
Lu, Yan
中科院分区：
文献类型：
--
作者：
Liu, Bin;Xiang, Liping;Lu, Yan
非酒精性脂肪性肝病（NAFLD）代表从单纯性脂肪变性（NAFL）到非酒精性脂肪性肝炎（NASH）的一系列慢性肝病。然而，NASH进展的分子机制仍不完全清楚。白色脂肪组织（WAT）已经成为重要的内分泌器官，并且不仅有助于NAFLD的初始阶段，而且有助于其严重性。在目前的研究中，通过转录组学分析，我们确定了在NASH小鼠的WAT中Sparcl 1（一种分泌型糖蛋白）的表达增加。血浆Sparcl 1水平同样升高，并与NASH患者的肝脏病理特征呈正相关。功能研究表明，长期注射重组Sparcl 1蛋白和过表达Sparcl 1都加重了小鼠的肝脏炎症和肝损伤。相反，Sparcl 1的基因消融、WAT中Sparcl 1的敲除以及Sparcl 1中和抗体治疗显著减轻了饮食诱导的NASH发病机制。Sparcl 1通过与Toll样受体4（TLR 4）结合并激活NF-κ B/p65信号通路促进C-C基序趋化因子配体2（CCL 2）在肝细胞中的表达。基因或药物阻断CCL 2/CCR 2通路可减弱Sparcl 1引起的肝脏炎症反应。因此，我们的研究结果证明了Sparcl 1在NASH进展中的重要作用，表明了治疗干预的潜在靶点。
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of chronic liver disease ranging from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH). However, the molecular mechanisms of NASH progression remain incompletely understood. White adipose tissue (WAT) has emerged as an important endocrine organ and contributes not only to the initial stage of NAFLD, but also to its severity. In the current study, through transcriptomic analysis we identified increased expression of Sparcl1, a secreted glycoprotein, in the WAT from NASH mice. Plasma Sparcl1 levels were similarly elevated and positively correlated with hepatic pathological features in NASH patients. Functional studies showed that both chronic injection of recombinant Sparcl1 protein and overexpression of Sparcl1 exaggerated hepatic inflammation and liver injury in mice. In contrast, genetic ablation of Sparcl1, knockdown of Sparcl1 in WAT, and treatment with a Sparcl1-neutralizing antibody dramatically alleviated diet-induced NASH pathogenesis. Mechanistically, Sparcl1 promoted the expression of C-C motif chemokine ligand 2 (CCL2) in hepatocytes through binding to Toll-like receptor 4 (TLR4) and activation of the NF-KB/p65 signaling pathway. Genetically or pharmacologically blocking the CCL2/CCR2 pathway attenuated the hepatic inflammatory response evoked by Sparcl1. Thus, our results demonstrated an important role for Sparcl1 in NASH progression, suggesting a potential target for therapeutic intervention.