Qiongyang Yu1, Xiurui Ma2,3, Yunan Wang1, Haozhe Shi1, Jian An3, Yuhui Wang1, Zhen Dong2,4,5, Yijing Lu2,6, Junbo Ge2,4,5,6, George Liu7,8, Xunde Xian9, Aijun Sun10,11,12,13. 1. Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, 100191, China. 2. Department of Cardiology, Zhongshan Hospital, Human Phenome Institute, Fudan University, Shanghai, 201203, China. 3. Department of Cardiology,, Shan Xi Cardiovascular Hospital, Taiyuan, 030024, China. 4. Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China. 5. NHC Key Laboratory of Viral Heart Diseases and Key Laboratory of Viral Heart Diseases, Shanghai, 200032, China. 6. Academy of Medical Sciences Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China. 7. Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, 100191, China. georgeliu@bjmu.edu.cn. 8. Hebei Invivo Biotech Co, Shijiazhuang, 050000, China. georgeliu@bjmu.edu.cn. 9. Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, 100191, China. xianxunde@bjmu.edu.cn. 10. Department of Cardiology, Zhongshan Hospital, Human Phenome Institute, Fudan University, Shanghai, 201203, China. sun.aijun@zs-hospital.sh.cn. 11. Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China. sun.aijun@zs-hospital.sh.cn. 12. NHC Key Laboratory of Viral Heart Diseases and Key Laboratory of Viral Heart Diseases, Shanghai, 200032, China. sun.aijun@zs-hospital.sh.cn. 13. Academy of Medical Sciences Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China. sun.aijun@zs-hospital.sh.cn.
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.
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.
Authors: David J Graham; Judy A Staffa; Deborah Shatin; Susan E Andrade; Stephanie D Schech; Lois La Grenade; Jerry H Gurwitz; K Arnold Chan; Michael J Goodman; Richard Platt Journal: JAMA Date: 2004-11-22 Impact factor: 56.272
Authors: E Link; S Parish; J Armitage; L Bowman; S Heath; F Matsuda; I Gut; M Lathrop; R Collins Journal: N Engl J Med Date: 2008-07-23 Impact factor: 91.245
Authors: Daniel Q Li; Richard B Kim; Eric McArthur; Jamie L Fleet; Robert A Hegele; Baiju R Shah; Matthew A Weir; Amber O Molnar; Stephanie Dixon; Jack V Tu; Sonia Anand; Amit X Garg Journal: PLoS One Date: 2016-03-08 Impact factor: 3.240