Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands.
Department of Biomedical Engineering, Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Radiology & Nuclear Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
Biochem Biophys Res Commun. 2020 Apr 2;524(2):510-515. doi: 10.1016/j.bbrc.2020.01.067. Epub 2020 Feb 1.
Mouse models are a crucial and often used tool to provide insight into the underlying mechanisms of human atherosclerosis. However, mice profoundly differ from humans in lipoprotein synthesis and metabolism, key factors in atherosclerotic plaque formation. Mouse models often require genetic and dietary modifications to mimic human pathophysiology, shifting from a high-density lipoprotein to an low-density lipoprotein dominant lipoprotein profile. We examined the suitability of mice with a humanized liver as a model for lipoprotein studies and studies on plaque formation, given the central role of hepatocytes in lipoprotein synthesis and metabolism. Our results show a progressive humanization of the mouse liver and a humanized lipoprotein profile. However, no atherosclerotic plaque formation was observed in the studied time frame, despite presence of functional macrophages and application of a high cholesterol western-type diet. The humanized-liver mouse model therefore might require further modifications to induce atherosclerosis, yet seems a valuable model for in vivo studies on lipoprotein metabolism.
小鼠模型是深入了解人类动脉粥样硬化潜在机制的重要且常用的工具。然而，在脂蛋白合成和代谢方面，小鼠与人类存在显著差异，而脂蛋白合成和代谢是动脉粥样硬化斑块形成的关键因素。为了模拟人类的病理生理学，小鼠模型通常需要进行基因和饮食修饰，从高密度脂蛋白（HDL）为主的脂蛋白谱转变为低密度脂蛋白（LDL）为主的脂蛋白谱。鉴于肝细胞在脂蛋白合成和代谢中的核心作用，我们研究了具有人源化肝脏的小鼠作为脂蛋白研究和斑块形成模型的适用性。我们的结果表明，小鼠肝脏的人源化程度逐渐增加，且出现人源化的脂蛋白谱。然而，尽管存在功能性巨噬细胞且应用了高胆固醇的西方饮食，在研究的时间范围内仍未观察到动脉粥样硬化斑块形成。因此，人源化肝脏小鼠模型可能需要进一步修饰以诱导动脉粥样硬化，但它似乎是用于脂蛋白代谢体内研究的有价值的模型。
