Dietary Cholesterol is Responsible for Statin-Induced Hepatic Toxicity in Experimental Hamsters and Chinese Cohort Studies

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Background: Statins are the inhibitors of HMG-CoA reductase in cholesterol synthesis as widely used lipid-lowering drugs. The major side-effects of statins include muscle- and liver- related toxicity. Muscle-toxicity is highly associated with the polymorphism of CYP predictable by pharmacogenomics. However, the mechanisms of hepatotoxicity is not well understood. Due to the differences in cholesterol metabolism, statins are well tolerated in mice. In contrast, hamsters exhibit metabolic traits close to humans and would be suitable to study hepatotoxicity of statins. Methods: We investigated the effect of statins on liver damage in high cholesterol diet (HCD)-fed wild-type (WT) hamsters, LDLR knockout (LDLR -/- ) hamsters with spontaneous hypercholesterolemia. Two cohorts of clinical subjects (Clinical registry number: 2017001) on statins were recruited for direct (assessment of cholesterol intake individually, n=44) and indirect (party meal times/holiday season, n=1,993) examination of dietary cholesterol intake and liver damage indicated by elevation of ALT. Results: Statins at a dose of 10mg/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 human studies, we observed that the incidence of hepatic toxicity in patients with a long-term statin treatment was higher in those who had more dietary cholesterol intake and in those who ate more during a Chinese holiday. Conclusions: Our results for the first time propose a hypothesis that dietary or exogenous, but not endogenous cholesterol, significantly contributes to the statin-related hepatotoxicity, then providing a valuable insight into the clinical use of statins. Funding: This project was supported by NSFC 31520103909 and 91739105 to G.L.; National KeyResearch and Development Program of China (2016YFE0126000), NSFC 81570787 and 81770449 to Y.W. G.L. is a fellow at the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University. Declaration of Interest: The authors declare no conflict of interest. Ethical Approval: The study protocol was approved by the ethics committee of Shanxi Cardiovascular Hospital (Clinical registry number: 2017001), and the written informed consent was provided by each patient at the time of registration. All experimental procedures were conducted under the guide of Care and Use of Laboratory Animals published by the US National Institutes of Health (No.85Y23, revised 1996) and were approved by the Animal Care Committee of Peking University Health Science Center (LA2010-059)