Dietary Cholesterol Exacerbates Statin-Induced Hepatic Toxicity in Syrian Golden Hamsters and in Patients in an Observat
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ORIGINAL ARTICLE
Dietary Cholesterol Exacerbates Statin-Induced Hepatic Toxicity in Syrian Golden Hamsters and in Patients in an Observational Cohort Study Qiongyang Yu 1 & Xiurui Ma 2,3 & Yunan Wang 1 & Haozhe Shi 1 & Jian An 3 & Yuhui Wang 1 & Zhen Dong 2,4,5 & Yijing Lu 2,6 & Junbo Ge 2,4,5,6 & George Liu 1,7 & Xunde Xian 1 & Aijun Sun 2,4,5,6 Accepted: 20 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords Statins . Hepatotoxicity . Hypercholesterolemia . Hamster Qiongyang Yu and Xiurui Ma contributed equally to this work. Xunde Xian is the Lead contact Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10557-020-07060-3) contains supplementary material, which is available to authorized users. * George Liu [email protected]
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
Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beiji
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