非酒精性脂肪肝（NAFLD）已成为全球最常见的慢性疾病。它是一种与肥胖相关的脂毒性肝损伤，可引起胰岛素抵抗和慢性炎症反应，最终进展为非酒精性脂肪性肝炎（NASH）。研究表明，拮抗CCR2/CCR5信号能够显著改善肥胖诱导的胰岛素抵抗和NASH。然而，关于CCR1调控胰岛素抵抗和NASH的研究却罕有报道。我们前期研究结果表明CCR1在NASH肝脏中表达上调；CCR1拮抗剂BX471能够显著降低M1巨噬细胞标记基因的表达和ROS的产量。因此，我们推测CCR1在NASH病变过程中具有重要作用。由此提出“CCR1通过调控ROS诱导Kupffer细胞M1极化进而促进NASH的发生和发展”这一假说。我们拟在前期研究的基础上，利用细胞模型结合动物模型及临床信息，阐明CCR1调控NASH病变的分子机制。研究结果不仅有助于加深对CCR1信号通路功能的了解，而且有助于催生NASH新的防治手段。

Nonalcoholic fatty liver disease (NAFLD) has become a global epidemic. It is an obesity-related lipotoxic liver injury associated with hepatic lipid accumulation that can induce systemic insulin resistance and progression to nonalcoholic steatohepatitis (NASH). Chemokines and their corresponding receptors exhibiting various physiological and pathological properties have been discovered. Therefore, activating or antagonizing chemokine receptor is expected to be used for treating the related diseases. It has been reported that loss of CCR2/CCR5 prevents obesity-induced insulin resistance and NASH. However, the contribution of CCR1 to insulin resistance and NASH has yet to be determined. More recently, preliminary data have shown that CCR1 is upregulated in NASH patients. Moreover, inhibition of CCR1 by BX471 attenuated M1-markers expression and ROS production in macrophages. Thus, we anticipate that CCR1 induces Kupffer cell M1-polarization by elevating ROS generation in the progression of NASH. Utilizing the Raw264.7 cells, diet-induced NASH model of mice in combination with clinical specimens, we are going to elucidate the molecular mechanisms of CCR1 modulating the pathogenesis of NASH. Overall, our findings will not only facilitate our understanding of the molecular mechanism for CCR1 regulation of NASH, but also provide the solid basis for utilizing CCR1 signaling as the target for effective prevention and therapy of NASH.