Abstract
Statins, which are revolutionized cholesterol-lowing agents, have been reported to have unfavorable effects on the liver. Inflammatory stress is a susceptibility factor for drug-induced liver injury. This study investigated whether inflammatory stress sensitized the liver to statin-induced toxicity in mice and explored the underlying mechanisms. We used casein injection in ApoE-/- mice to induce inflammatory stress. Half of the mice were orally administered atorvastatin (10mg/kg/d) for 8 weeks. The results showed that casein injection increased the levels of serum pro-inflammatory cytokines (IL-6 and TNFα). Atorvastatin treatment increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in casein injection mice. Moreover, atorvastatin treatment exacerbated hepatic steatosis, inflammation and fibrosis, as well as increased hepatic reactive oxygen species (ROS) and malondialdehyde in casein injection mice. However, above changes were not observed in atorvastatin treated alone mice. The protein expression of liver nuclear factor erythroid 2-related factor 2 (Nrf2) and the mRNA expressions of Nrf2 target genes were increased, together with the enhancement of activities of hepatic catalase and superoxide dismutase in atorvastatin treated alone mice, but these antioxidant responses were lost in mice treated with atorvastatin under inflammatory stress. This study demonstrates that atorvastatin exacerbates the liver injury under inflammatory stress, which may be associated with the loss of adaptive antioxidant response mediated by Nrf2.
Highlights
Hypercholesterolemia, characterized by a high level of circulating low-density lipoprotein cholesterol (LDL-C), is a crucial risk factor for cardiovascular disease (CVD)[1]
Serum levels of pro-inflammatory cytokines (IL-6 and tumor necrosis factorα (TNFα)) were significant increased in mice with casein injection compared to those without casein injection (Table 2), suggesting that chronic inflammation was successfully induced in ApoE-/- mice
Serum LDL-C levels were significantly decreased in casein injected mice compared to controls (Table 2), which is consistent with our previous studies[19]
Summary
Hypercholesterolemia, characterized by a high level of circulating low-density lipoprotein cholesterol (LDL-C), is a crucial risk factor for cardiovascular disease (CVD)[1]. Statins are a class of drugs which exhibit a powerful hypocholesterolemic effect by inhibiting the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR). Treatment with statins has been reported to markedly reduce morbidities and mortalities of major cardiovascular events in patients[2, 3]. Research and Frontier Technology (No cstc2015jcyjBX0044), http://www.cstc.gov.cn/, YC received the funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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