Chronopharmacology of simvastatin on hyperlipidaemia in high-fat diet-fed obese mice.
Chronopharmacology of simvastatin on hyperlipidaemia in high-fat diet-fed obese mice.
复制标题
辛伐他汀对高脂饮食肥胖小鼠高脂血症的时间药理学
DOI：
10.1111/jcmm.15709
复制
发表时间：
2020-09
影响因子：
5.3
通讯作者：
Liu C
中科院分区：
文献类型：
--
作者：
Li H;Rabearivony A;Zhang W;Chen S;An X;Liu C
时辰药理学是指利用生理昼夜节律来优化药物的给药时间，从而提高药物的疗效和安全性，或减少不良反应。辛伐他汀是治疗高胆固醇血症、高脂血症和冠状动脉疾病的最广泛的处方药之一。关于辛伐他汀给药的时间有相互矛盾的说法，并且仍然没有令人信服的实验证据。因此，我们的目的是检查不同的给药时间是否会影响辛伐他汀的疗效。高脂饲料喂养的小鼠分别在时间表时间1（ZT 1）或ZT 13接受辛伐他汀治疗9周。无论给药时间如何，辛伐他汀对这些肥胖小鼠均显示出稳健的抗高胆固醇血症和抗高脂血症作用。然而，与ZT 1相比，在ZT 13时给予辛伐他汀在降低血清总胆固醇、甘油三酯、非酯化游离脂肪酸和LDL胆固醇水平以及改善肝脏病理特征方面更有效。在可能的机制方面，我们发现辛伐他汀在体内没有改变肝脏生物钟基因的表达，尽管它在体外不能改变Per2：：Luc U2OS和Bmal 1：：Luc U2OS细胞振荡模式的周期、相位和幅度。与此相反，辛伐他汀以昼夜节律的方式调节Hmgcr、Mdr1和Slco2b1的表达，这可能有助于药物的时间药理学功能。综上所述，我们提供了确凿的证据，表明不同的给药时间会影响辛伐他汀的降脂作用。
The chronopharmacology refers to the utilization of physiological circadian rhythms to optimize the administration time of drugs, thus increasing their efficacy and safety, or reducing adverse effects. Simvastatin is one of the most widely prescribed drugs for the treatment of hypercholesterolaemia, hyperlipidemia and coronary artery disease. There are conflicting statements regarding the timing of simvastatin administration, and convincing experimental evidence remains unavailable. Thus, we aimed to examine whether different administration times would influence the efficacy of simvastatin. High‐fat diet‐fed mice were treated with simvastatin at zeitgeber time 1 (ZT1) or ZT13, respectively, for nine weeks. Simvastatin showed robust anti‐hypercholesterolaemia and anti‐hyperlipidemia effects on these obese mice, regardless of administration time. However, simvastatin administrated at ZT13, compared to ZT1, was more functional for decreasing serum levels of total cholesterol, triglycerides, non‐esterified free fatty acids and LDL cholesterol, as well as improving liver pathological characteristics. In terms of possible mechanisms, we found that simvastatin did not alter the expression of hepatic circadian clock gene in vivo, although it failed to change the period, phase and amplitude of oscillation patterns in Per2::Luc U2OS and Bmal1::Luc U2OS cells in vitro. In contrast, simvastatin regulated the expression of Hmgcr, Mdr1 and Slco2b1 in a circadian manner, which potentially contributed to the chronopharmacological function of the drug. Taken together, we provide solid evidence to suggest that different administration times affect the lipid‐lowering effects of simvastatin.
登录
查看更多内容
DOI：
10.1126/science.aah4967
发表时间：
2016-11-25
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Panda S
通讯作者：
Panda S
DOI：
10.1073/pnas.1408886111
发表时间：
2014-11-11
影响因子：
11.1
作者：
Zhang, Ray;Lahens, Nicholas F.;Hogenesch, John B.
通讯作者：
Hogenesch, John B.
影响因子：
3.7
作者：
Hochman, JH;Pudvah, N;Prueksaritanont, T
通讯作者：
Prueksaritanont, T
影响因子：
3.2
作者：
Kim, Sang-Hyun;Kim, Min-Kyung;Park, Seong Hoon
通讯作者：
Park, Seong Hoon
影响因子：
--
作者：
Wallace, A;Chinn, D;Rubin, G
通讯作者：
Rubin, G