Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA.
Lexington VA Medical Center, Lexington, Kentucky, USA.
Liver Int. 2022 Apr;42(4):829-841. doi: 10.1111/liv.15182. Epub 2022 Feb 15.
BACKGROUND & AIMS: With the epidemic burden of obesity and metabolic diseases, nonalcoholic fatty liver disease (NAFLD) including steatohepatitis (NASH) has become the most common chronic liver disease in the western world. NASH may progress to cirrhosis and hepatocellular carcinoma. Currently, no treatment is available for NASH. Therefore, finding a therapy for NAFLD/NASH is in urgent need. Previously we have demonstrated that mice lacking CD47 or its ligand thrombospondin1 (TSP1) are protected from obesity-associated NALFD. This suggests that CD47 blockade might be a novel treatment for obesity-associated metabolic disease. Thus, in this study, the therapeutic potential of an anti-CD47 antibody in NAFLD progression was determined.
Both diet-induced NASH mouse model and human NASH organoid model were utilized in this study. NASH was induced in mice by feeding with diet enriched with fat, fructose and cholesterol (AMLN diet) for 20 weeks and then treated with anti-CD47 antibody or control IgG for 4 weeks. Body weight, body composition and liver phenotype were analysed.
We found that anti-CD47 antibody treatment did not affect mice body weight, fat mass or liver steatosis. However, liver immune cell infiltration, inflammation and fibrosis were significantly reduced by anti-CD47 antibody treatment. In vitro data further showed that CD47 blockade prevented hepatic stellate cell activation and NASH progression in a human NASH organoid model.
Collectively, these data suggest that anti-CD47 antibody might be a new therapeutic option for obesity-associated NASH and liver fibrosis.
随着肥胖和代谢性疾病负担的增加，非酒精性脂肪性肝病（NAFLD）包括脂肪性肝炎（NASH）已成为西方国家最常见的慢性肝病。NASH 可能进展为肝硬化和肝细胞癌。目前，尚无针对 NASH 的治疗方法。因此，寻找治疗 NAFLD/NASH 的方法迫在眉睫。先前我们已经证明，缺乏 CD47 或其配体血小板反应蛋白 1（TSP1）的小鼠可免受肥胖相关的 NALFD 影响。这表明 CD47 阻断可能是肥胖相关代谢性疾病的一种新的治疗方法。因此，在这项研究中，确定了抗 CD47 抗体在 NAFLD 进展中的治疗潜力。
本研究同时使用了饮食诱导的 NASH 小鼠模型和人 NASH 类器官模型。通过用富含脂肪、果糖和胆固醇的饮食（AMLN 饮食）喂养 20 周来诱导小鼠 NASH，并在 4 周内用抗 CD47 抗体或对照 IgG 进行治疗。分析体重、身体成分和肝脏表型。
我们发现抗 CD47 抗体治疗并不影响小鼠体重、脂肪量或肝脂肪变性。然而，抗 CD47 抗体治疗显著减少了肝脏免疫细胞浸润、炎症和纤维化。体外数据进一步表明，CD47 阻断可防止肝星状细胞活化和人 NASH 类器官模型中的 NASH 进展。
总之，这些数据表明，抗 CD47 抗体可能是肥胖相关 NASH 和肝纤维化的一种新的治疗选择。
