Baek Ji Sun, Fang Longhou, Li Andrew C, Miller Yury I
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Cholesterol. 2012;2012:564705. doi: 10.1155/2012/564705. Epub 2012 May 30.
Cholesterol-fed zebrafish is an emerging animal model to study metabolic, oxidative, and inflammatory vascular processes relevant to pathogenesis of human atherosclerosis. Zebrafish fed a high-cholesterol diet (HCD) develop hypercholesterolemia and are characterized by profound lipoprotein oxidation and vascular lipid accumulation. Using optically translucent zebrafish larvae has the advantage of monitoring vascular pathology and assessing the efficacy of drug candidates in live animals. Thus, we investigated whether simvastatin and ezetimibe, the principal drugs used in management of hypercholesterolemia in humans, would also reduce cholesterol levels in HCD-fed zebrafish larvae. We found that ezetimibe was well tolerated by zebrafish and effectively reduced cholesterol levels in HCD-fed larvae. In contrast, simvastatin added to water was poorly tolerated by zebrafish larvae and, when added to food, had little effect on cholesterol levels in HCD-fed larvae. Combination of low doses of ezetimibe and simvastatin had an additive effect in reducing cholesterol levels in zebrafish. These results suggest that ezetimibe exerts in zebrafish a therapeutic effect similar to that in humans and that the hypercholesterolemic zebrafish can be used as a low-cost and informative model for testing new drug candidates and for investigating mechanisms of action for existing drugs targeting dyslipidemia.
喂食胆固醇的斑马鱼是一种新兴的动物模型，用于研究与人类动脉粥样硬化发病机制相关的代谢、氧化和炎症性血管过程。喂食高胆固醇饮食（HCD）的斑马鱼会出现高胆固醇血症，其特征是脂蛋白深度氧化和血管脂质积累。使用光学透明的斑马鱼幼虫具有监测血管病理和评估候选药物在活体动物中的疗效的优势。因此，我们研究了人类高胆固醇血症管理中使用的主要药物辛伐他汀和依折麦布是否也能降低喂食HCD的斑马鱼幼虫的胆固醇水平。我们发现依折麦布在斑马鱼中耐受性良好，并能有效降低喂食HCD的幼虫的胆固醇水平。相比之下，添加到水中的辛伐他汀在斑马鱼幼虫中耐受性较差，而添加到食物中时，对喂食HCD的幼虫的胆固醇水平几乎没有影响。低剂量依折麦布和辛伐他汀的组合在降低斑马鱼胆固醇水平方面具有相加作用。这些结果表明，依折麦布在斑马鱼中发挥的治疗作用与在人类中相似，并且高胆固醇血症斑马鱼可作为一种低成本且信息丰富的模型，用于测试新的候选药物以及研究现有针对血脂异常药物的作用机制。
