Dietary Cholesterol Exacerbates Statin-Induced Hepatic Toxicity in Syrian Golden Hamsters and in Patients in an Observational Cohort Study
Dietary Cholesterol Exacerbates Statin-Induced Hepatic Toxicity in Syrian Golden Hamsters and in Patients in an Observational Cohort Study
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在一项观察性队列研究中，膳食胆固醇会加剧叙利亚金仓鼠和患者中他汀类药物引起的肝毒性
DOI：
10.1007/s10557-020-07060-3
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发表时间：
2020-08
影响因子：
3.4
通讯作者：
Aijun Sun
中科院分区：
文献类型：
--
作者：
Qiongyang Yu;Xiurui Ma;Yunan Wang;Haozhe Shi;Jian An;Yuhui Wang;Zhen Dong;Yijing Lu;Junbo Ge;George Liu;Xunde Xian;Aijun Sun
目的他汀类药物是3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶的抑制剂，该酶参与胆固醇的合成。他汀类药物的主要副作用包括肌肉和肝脏相关毒性。肌肉毒性与细胞色素P450蛋白（CYP）多态性高度相关，如药物基因组学所预测。然而，肝毒性的机制还不清楚。由于胆固醇代谢的差异，他汀类药物在小鼠中耐受性良好。相比之下，仓鼠表现出类似于人类的代谢特征，适合于研究他汀类药物的肝毒性。MethodsWe调查了瑞舒伐他汀（RSV）对野生型（WT）仓鼠肝损伤的影响，喂养高胆固醇饮食（HCD）和低密度脂蛋白受体敲除（LDLR-/-）仓鼠，自发性高胆固醇血症。两个临床受试者队列（临床注册号：2017001）服用阿托伐他汀（ATV），招募直接（单独评估胆固醇摄入量，n= 44）和间接（庆祝餐/假日季节，n= 1993）检查饮食胆固醇摄入量和肝损伤，如丙氨酸氨基转移酶（ALT）的升高所示。结果10 mg/kg剂量的RSV仅在HCD喂养的WT仓鼠中引起致命的肝损伤，而具有相同胆固醇水平的LDLR−/−仓鼠对这种毒性作用具有抵抗力。在人类的研究中，我们观察到，在接受长期ATV治疗的患者肝毒性的发病率较高的患者，更大的饮食胆固醇摄入量和谁消耗更多的食物在中国holiday.ConclusionOur研究结果提出，第一次，饮食胆固醇显着有助于他汀类药物相关的肝毒性，他汀类药物的临床使用提供了宝贵的见解。
PurposeStatins are inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, which is involved in cholesterol synthesis. The major side effects of statins include muscle- and liver-related toxicity. Muscle toxicity is highly associated with polymorphisms in cytochrome P450 proteins (CYPs), as predicted by pharmacogenomics. However, the mechanisms of hepatotoxicity are not well understood. Due to differences in cholesterol metabolism, statins are well tolerated in mice. In contrast, hamsters exhibit metabolic traits similar to humans and are suitable for studying the hepatotoxicity of statins.MethodsWe investigated the effect of rosuvastatin (RSV) on liver damage in wild-type (WT) hamsters fed a high-cholesterol diet (HCD) and LDLR knockout (LDLR−/−) hamsters that developed spontaneous hypercholesterolemia. Two cohorts of clinical subjects (clinical registry number: 2017001) taking atorvastatin (ATV) were recruited for direct (assessment of cholesterol intake individually,n= 44) and indirect (celebratory meals/holiday season,n= 1993) examination of dietary cholesterol intake and liver damage, as indicated by elevation of alanine aminotransferase (ALT).ResultsRSV at a dose of 10 mg/kg caused fatal liver damage only in HCD-fed WT hamsters, while LDLR−/−hamsters with the same cholesterol levels were resistant to this toxic effect. In the human studies, we observed that the incidence of hepatic toxicity in patients receiving long-term ATV treatment was higher in patients with greater dietary cholesterol intake and in patients who consumed more food during Chinese holidays.ConclusionOur results propose, for the first time, that dietary cholesterol significantly contributes to statin-related hepatotoxicity, providing valuable insight into the clinical use of statins.
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DOI：
--
发表时间：
1989-02
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
D. Kornbrust;J. MacDonald;C. Peter;D. M. Duchai;R. Stubbs;J. Germershausen;A. Alberts
通讯作者：
D. Kornbrust;J. MacDonald;C. Peter;D. M. Duchai;R. Stubbs;J. Germershausen;A. Alberts
影响因子：
6.5
作者：
J. Dietschy;S. Turley;D. Spady
通讯作者：
J. Dietschy;S. Turley;D. Spady
影响因子：
25.7
作者：
Bjornsson, Einar;Jacobsen, Elin I.;Kalaitzakis, Evangelos
通讯作者：
Kalaitzakis, Evangelos
LDL 受体基因消除仓鼠：具有显性遗传和饮食诱导的冠状动脉粥样硬化的家族性高胆固醇血症的啮齿动物模型
影响因子：
11.1
作者：
Guo X;Gao M;Wang Y;Lin X;Yang L;Cong N;An X;Wang F;Qu K;Yu L;Wang Y;Wang J;Zhu H;Xian X;Liu G
通讯作者：
Liu G
影响因子：
4.4
作者：
Maria Tzefos;J. L. Olin
通讯作者：
Maria Tzefos;J. L. Olin