| Title | Dietary Cholesterol Exacerbates Statin-Induced Hepatic Toxicity in Syrian Golden Hamsters and in Patients in an Observational Cohort Study |
| Authors | Yu, Qiongyang Ma, Xiurui Wang, Yunan Shi, Haozhe An, Jian Wang, Yuhui Dong, Zhen Lu, Yijing Ge, Junbo Liu, George Xian, Xunde Sun, Aijun |
| Affiliation | Peking Univ, Inst Cardiovasc Sci, Minist Educ, Beijing 100191, Peoples R China Peking Univ, Key Lab Mol Cardiovasc Sci, Minist Educ, Beijing 100191, Peoples R China Fudan Univ, Zhongshan Hosp, Human Phenome Inst, Dept Cardiol, Shanghai 201203, Peoples R China Shan Xi Cardiovasc Hosp, Dept Cardiol, Taiyuan 030024, Peoples R China Shanghai Inst Cardiovasc Dis, Shanghai 200032, Peoples R China NHC Key Lab Viral Heart Dis, Shanghai 200032, Peoples R China Key Lab Viral Heart Dis, Shanghai 200032, Peoples R China Fudan Univ, Acad Med Sci Inst Biomed Sci, Shanghai 200032, Peoples R China Hebei Inv Biotech Co, Shijiazhuang 050000, Hebei, Peoples R China |
| Keywords | A REDUCTASE INHIBITOR HMG-COA REDUCTASE BODY-SURFACE AREA LIVER LOVASTATIN |
| Issue Date | Aug-2020 |
| Publisher | CARDIOVASCULAR DRUGS AND THERAPY |
| Abstract | Purpose Statins 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. Methods We 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). Results RSV 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. Conclusion Our results propose, for the first time, that dietary cholesterol significantly contributes to statin-related hepatotoxicity, providing valuable insight into the clinical use of statins. |
| URI | http://hdl.handle.net/20.500.11897/607549 |
| ISSN | 0920-3206 |
| DOI | 10.1007/s10557-020-07060-3 |
| Indexed | SCI(E) |
| Appears in Collections: | 基础医学院 分子心血管学教育部重点实验室 |
