Ogawa Yoshihiro, Suganami Takayoshi, Itoh Michiko, Tanaka Miyako
Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan
Japan Agency for Medical Research and Development,, CREST, Tokyo, 100-0004, Japan
Non-alcoholic steatohepatitis (NASH) is closely associated with progression to liver cirrhosis and hepatocellular carcinoma. We reported that melanocortin 4 receptor–deficient mice (MC4R-KO mice), when fed a high-fat diet, provide a novel rodent model of NASH. Recently, we have identified a unique histological feature termed “hepatic crown-like structures” (hCLS) in the livers of MC4R-KO mice and NASH patients. In hCLS, CD11c-positive macrophages aggregate to surround hepatocytes with large lipid droplets, similar to the “crown-like structure (CLS)” described in obese adipose tissue. Interestingly, we have recently reported that macrophage-induced C-type lectin (Mincle) is involved in CLS formation and fibrogenic gene expression in obese adipose tissue, suggesting the pathophysiologic role of CLS in obesity-induced adipose tissue fibrosis. Collectively, our data provide evidence that hCLS serves as an origin of hepatic inflammation and fibrosis during the progression from simple steatosis to NASH and thus helps in elucidation of the pathogenesis of NASH, pursuit of specific biomarkers, and evaluation of potential therapeutic strategies.
非酒精性脂肪性肝炎（NASH）与肝硬化和肝细胞癌的进展密切相关。我们报道，黑色素皮质素4受体缺陷小鼠（MC4R-KO小鼠）在喂食高脂饮食时，可提供一种新型的NASH啮齿动物模型。最近，我们在MC4R-KO小鼠和NASH患者的肝脏中发现了一种独特的组织学特征，称为“肝冠样结构”（hCLS）。在hCLS中，CD11c阳性巨噬细胞聚集以围绕含有大脂滴的肝细胞，类似于肥胖脂肪组织中描述的“冠样结构”（CLS）。有趣的是，我们最近报道巨噬细胞诱导的C型凝集素（Mincle）参与肥胖脂肪组织中CLS的形成和纤维化基因表达，提示CLS在肥胖诱导的脂肪组织纤维化中的病理生理作用。总体而言，我们的数据提供了证据，表明hCLS在从单纯脂肪变性进展为NASH的过程中作为肝脏炎症和纤维化的起源，从而有助于阐明NASH的发病机制、寻找特定生物标志物以及评估潜在治疗策略。
