Induction of obesity impairs reverse cholesterol transport in ob/ob mice

ObjectivesObesity is an independent risk factor for cardiovascular disease. Reverse cholesterol transport (RCT) is an important cardioprotective mechanism. This study aimed to investigate RCT changes in a murine model of obesity.MethodsOb/ob and control mice were injected with [3H]-cholesterol-labelled macrophages and cholesterol accumulation quantified after 48 h. Ex vivo, cholesterol efflux and uptake were determined in hepatic and adipose tissues.ResultsOb/ob mice had more labelled cholesterol in their plasma (86%, pob/ob mice (serum, 33%; apoB-depleted plasma, 14%, pEx vivo it was found that cholesterol uptake was significantly lower into the livers and adipose tissue of ob/ob mice, compared to non-obese wildtype controls. Furthermore, ex vivo cholesterol efflux was reduced in ob/ob liver and adipose tissue towards apoA-I and HDL. Consistent with this, protein levels of SR-BI and ABCG1 were significantly lower in ob/ob hepatic and adipose tissue than in wildtype mice. Finally, labelled cholesterol concentrations were lower in ob/ob bile (67%, pConclusionObesity causes impairment in RCT due to reduced plasma cholesterol uptake and efflux by hepatocytes and adipocytes. A reduction in the capacity for plasma cholesterol clearance may partly account for increased CVD risk with obesity.

研究目的
肥胖是心血管疾病的独立危险因素。胆固醇逆转运（Reverse Cholesterol Transport, RCT）是重要的心脏保护机制。本研究旨在探究肥胖小鼠模型中的胆固醇逆转运变化。

研究方法
向ob/ob肥胖小鼠及野生型对照小鼠注射[³H]-胆固醇标记的巨噬细胞，于48小时后定量检测胆固醇蓄积水平。体外实验中，检测肝脏与脂肪组织的胆固醇摄取及外流能力。

研究结果
与对照小鼠相比，ob/ob小鼠血浆内标记胆固醇水平升高86%（p<0.05）；且标记胆固醇在各组织间的分布存在差异，ob/ob小鼠血清中标记胆固醇水平升高33%，脱载脂蛋白B（apoB）血浆中升高14%（p<0.05）。体外实验发现，与非肥胖野生型对照相比，ob/ob小鼠肝脏与脂肪组织的胆固醇摄取能力显著降低。此外，ob/ob小鼠肝脏及脂肪组织向载脂蛋白A-I（apoA-I）和高密度脂蛋白（HDL）的胆固醇外流能力均出现下降。与此一致的是，ob/ob小鼠肝脏与脂肪组织中清道夫受体B类1型（SR-BI）及ATP结合盒转运蛋白G1（ABCG1）的蛋白水平均显著低于野生型小鼠。最终，ob/ob小鼠胆汁中的标记胆固醇浓度降低67%（p<0.05）。

研究结论
肥胖会通过削弱肝细胞与脂肪细胞对血浆胆固醇的摄取及外流能力，损伤胆固醇逆转运功能。血浆胆固醇清除能力的下降，可部分解释肥胖人群心血管疾病风险升高的现象。