Inflammation is one of the hallmarks of non-alcoholic steatohepatitis. CD47 is a widely expressed transmembrane protein that signals through inhibitory receptor signal regulatory protein α (SIRPα) to inhibit macrophage activation and phagocytosis. In this study, we sought to investigate the role of CD47 in hepatosteatosis and fibrosis induced by a chronic high-fat diet (HFD), by comparing disease development in wild-type (WT) and CD47KO mice fed HFD for 40 weeks. The HFD induced remarkably more severe hepatic steatosis and fibrosis but less body weight gain and less subcutaneous fat accumulation in CD47KO mice compared to WT mice. Liver tissues from HFD-fed CD47KO mice exhibited enhanced inflammation characterized by increased proinflammatory cytokine production and increased nuclear factor-κB (NF-κB) activation compared to similarly fed WT mice. Although higher expression of apolipoproteins was observed in CD47KO mice compared to WT mice under a low-fat diet (LFD), HFD-fed WT and CD47KO mice showed comparably prominent downregulation of these apolipoprotein genes, suggesting that the marked difference observed in lipid accumulation and hepatosteatosis between these mice cannot be explained by changes in apolipoproteins. Like apolipoproteins, sirtuin 1 (SIRT1) and peroxisome proliferator activated receptor alpha (PPARα), which are involved in regulation of both lipid metabolism and inflammation, were more highly expressed in CD47KO than WT mice under LFD but more severely suppressed in CD47KO than in WT mice under HFD. Taken together, our results indicate that CD47 plays a significant role in the pathogenesis of HFD-induced hepatosteatosis and fibrosis through its role in regulation of inflammation and lipid metabolism.

炎症是非酒精性脂肪性肝炎的标志之一。CD47是一种广泛表达的跨膜蛋白，可通过抑制性受体信号调节蛋白α（SIRPα）发出信号，从而抑制巨噬细胞的活化和吞噬作用。在这项研究中，我们试图通过比较喂食HFD 40周的野生型（WT）和CD47KO小鼠的疾病发展情况，来研究CD47在慢性高脂饮食（HFD）诱发的肝硬皮病和纤维化中的作用。与WT小鼠相比，HFD诱导CD47KO小鼠的肝脏脂肪变性和纤维化更为严重，但体重增加较少，皮下脂肪蓄积较少。与类似喂养的WT小鼠相比，来自HFD喂养的CD47KO小鼠的肝组织表现出炎症增强，其特征在于促炎性细胞因子生成增加和核因子-κB（NF-κB）活化增加。尽管在低脂饮食（LFD）下与野生型小鼠相比，CD47KO小鼠中载脂蛋白的表达较高，但由HFD喂养的野生型和CD47KO小鼠对这些载脂蛋白基因的表达却相对明显下调，这表明在脂质蓄积和脂肪沉积方面观察到明显差异。这些小鼠之间的肝脂肪变性不能通过载脂蛋白的变化来解释。像载脂蛋白一样，参与脂代谢和炎症调节的sirtuin 1（SIRT1）和过氧化物酶体增殖物激活的受体α（PPARα）在LFD下比WT小鼠在CD47KO中的表达更高，但在CD47KO中比在WT中受到更严重的抑制HFD下的小鼠。在一起