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-κB/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.

中文翻译：

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Sparcl1 通过上调 CCL2 促进小鼠非酒精性脂肪性肝炎的进展

非酒精性脂肪性肝病 (NAFLD) 代表一系列慢性肝病，从单纯性脂肪变性 (NAFL) 到非酒精性脂肪性肝炎 (NASH)。然而，NASH 进展的分子机制仍不完全清楚。白色脂肪组织 (WAT) 已成为一种重要的内分泌器官，不仅有助于 NAFLD 的初始阶段，而且有助于其严重程度。在目前的研究中，通过转录组分析，我们发现 NASH 小鼠的 WAT 中 Sparcl1（一种分泌的糖蛋白）的表达增加。血浆 Sparcl1 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，重组 Sparcl1 蛋白的慢性注射和 Sparcl1 的过表达都夸大了小鼠的肝脏炎症和肝损伤。Sparcl1、WAT 中 Sparcl1 的敲低以及用 Sparcl1 中和抗体治疗显着减轻了饮食诱导的 NASH 发病机制。从机制上讲，Sparcl1 通过与 Toll 样受体 4 (TLR4) 结合和激活 NF-κB/p65 信号通路促进肝细胞中 CC 基序趋化因子配体 2 (CCL2) 的表达。基因或药理学阻断 CCL2/CCR2 通路减弱了 Sparcl1 引起的肝脏炎症反应。因此，我们的结果证明了 Sparcl1 在 NASH 进展中的重要作用，表明治疗干预的潜在目标。