Wang Ziyun, Niimi Manabu, Ding Qianzhi, Liu Zhenming, Wang Ling, Zhang Jifeng, Xu Jun, Fan Jianglin
Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
PLoS One. 2017 Aug 2;12(8):e0180772. doi: 10.1371/journal.pone.0180772. eCollection 2017.
Cholesteryl ester transfer protein (CETP) is a plasma protein that mediates bidirectional transfers of cholesteryl esters and triglycerides between low-density lipoproteins and high-density lipoproteins (HDL). Because low levels of plasma CETP are associated with increased plasma HDL-cholesterol, therapeutic inhibition of CETP activity is considered an attractive strategy for elevating plasma HDL-cholesterol, thereby hoping to reduce the risk of cardiovascular disease. Interestingly, only a few laboratory animals, such as rabbits, guinea pigs, and hamsters, have plasma CETP activity, whereas mice and rats do not. It is not known whether all CETPs in these laboratory animals are functionally similar to human CETP. In the current study, we compared plasma CETP activity and characterized the plasma lipoprotein profiles of these animals. Furthermore, we studied the three CETP molecular structures, physicochemical characteristics, and binding properties with known CETP inhibitors in silico. Our results showed that rabbits exhibited higher CETP activity than guinea pigs and hamsters, while these animals had different lipoprotein profiles. CETP inhibitors can inhibit rabbit and hamster CETP activity in a similar manner to human CETP. Analysis of CETP molecules in silico revealed that rabbit and hamster CETP showed many features that are similar to human CETP. These results provide novel insights into understanding CETP functions and molecular properties.
胆固醇酯转运蛋白（CETP）是一种血浆蛋白，介导低密度脂蛋白和高密度脂蛋白（HDL）之间胆固醇酯和甘油三酯的双向转运。由于血浆中低水平的CETP与血浆HDL胆固醇水平升高相关，因此对CETP活性进行治疗性抑制被认为是提高血浆HDL胆固醇的一种有吸引力的策略，从而有望降低心血管疾病风险。有趣的是，只有少数实验动物，如兔子、豚鼠和仓鼠，具有血浆CETP活性，而小鼠和大鼠则没有。目前尚不清楚这些实验动物中的所有CETP在功能上是否与人类CETP相似。在本研究中，我们比较了这些动物的血浆CETP活性，并对其血浆脂蛋白谱进行了表征。此外，我们在计算机模拟中研究了三种CETP的分子结构、物理化学特性以及与已知CETP抑制剂的结合特性。我们的结果表明，兔子的CETP活性高于豚鼠和仓鼠，而这些动物具有不同的脂蛋白谱。CETP抑制剂可以以与人类CETP相似的方式抑制兔子和仓鼠的CETP活性。计算机模拟对CETP分子的分析表明，兔子和仓鼠的CETP表现出许多与人类CETP相似的特征。这些结果为理解CETP的功能和分子特性提供了新的见解。
