Department of Advanced Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Lab Invest. 2012 Feb;92(2):265-81. doi: 10.1038/labinvest.2011.159. Epub 2011 Nov 7.
Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome that is characterized by steatosis, inflammation, and fibrosis, and may progress to cirrhosis and carcinoma. To investigate its pathogenic processes, we established a novel murine model for NASH by combination of a high-fat diet (HFD) and oxidized low-density lipoprotein (oxLDL). Mice that received HFD for 23 weeks showed hepatic steatosis, slight fibrosis, and a high level of lipid peroxidation compared with a regular diet (RD)-fed mice. Hepatic injury and elevated tumor necrosis factor (TNF)-α mRNA expression were also detected in these mice. Moreover, oxLDL administration to HFD-fed mice during weeks 21-23 not only aggravated hepatic steatosis, fibrosis, and lipid metabolism, but also resulted in intense inflammation, including severe hepatic injury and inflammatory cell infiltration, which are the typical histological features of NASH. Inflammation was accompanied by increased gene expression of TNF-α and interleukin (IL)-6. Additionally, the livers of RD-fed animals treated with oxLDL during weeks 21-23 were characterized by foamy macrophages and inflammatory cell infiltration along with an elevated IL-6 mRNA level. These results suggest that an increased oxidative state, including HFD-induced intracellular lipid peroxidation and its extracellular source from oxLDL, is the actual trigger for hepatic inflammation in which liver injury is mediated by TNF-α and inflammatory cell accumulation is dependent on IL-6. HFD and oxLDL also induced insulin resistance in mice; additionally, oxLDL downregulated insulin secretion. In this model, CD36 overexpression was observed in the hepatocytes of HFD-fed mice and those treated with HFD and oxLDL, and in the hepatic macrophages of RD-fed mice immediately after oxLDL treatment. In vitro experiments indicated a rapid and transient elevation of CD36 on macrophage plasma membrane in response to oxLDL. Our findings demonstrate that CD36 expressed on hepatocytes and hepatic macrophages mediates the pathophysiology of NASH.
非酒精性脂肪性肝炎（NASH）是代谢综合征的肝脏表现，其特征为脂肪变性、炎症和纤维化，并且可能进展为肝硬化和肝癌。为了研究其发病机制，我们通过高脂肪饮食（HFD）和氧化型低密度脂蛋白（oxLDL）的联合作用，建立了一种新的 NASH 小鼠模型。与正常饮食（RD）喂养的小鼠相比，接受 HFD 喂养 23 周的小鼠表现出肝脂肪变性、轻微纤维化和脂质过氧化水平升高。这些小鼠还检测到肝损伤和肿瘤坏死因子（TNF）-α mRNA 表达升高。此外，在第 21-23 周向 HFD 喂养的小鼠给予 oxLDL 不仅加重了肝脂肪变性、纤维化和脂质代谢，还导致了强烈的炎症，包括严重的肝损伤和炎症细胞浸润，这是 NASH 的典型组织学特征。炎症伴随着 TNF-α和白细胞介素（IL）-6 基因表达的增加。此外，在第 21-23 周给予 oxLDL 的 RD 喂养动物的肝脏表现为泡沫状巨噬细胞和炎症细胞浸润，同时 IL-6 mRNA 水平升高。这些结果表明，包括 HFD 诱导的细胞内脂质过氧化和 oxLDL 产生的细胞外来源在内的氧化状态增加是肝内炎症的实际触发因素，其中肝损伤由 TNF-α介导，炎症细胞积聚依赖于 IL-6。HFD 和 oxLDL 还导致小鼠胰岛素抵抗；此外，oxLDL 下调胰岛素分泌。在该模型中，在 HFD 喂养的小鼠和 HFD 和 oxLDL 处理的小鼠的肝细胞以及在 oxLDL 处理后立即接受 oxLDL 处理的 RD 喂养的小鼠的肝巨噬细胞中观察到 CD36 过表达。体外实验表明，oxLDL 迅速和短暂地上调巨噬细胞质膜上的 CD36。我们的研究结果表明，在肝实质细胞和肝巨噬细胞上表达的 CD36 介导了 NASH 的病理生理学。
