Astragaloside IV Alleviates Atorvastatin-Induced Hepatotoxicity via AMPK/SIRT1 Pathway

Abstract

<b><i>Introduction:</i></b> Atorvastatin (ATO) is often used to reduce blood lipids and prevent atherosclerosis, but excessive use of ATO will lead to hepatotoxicity. This paper investigated the effects of astragaloside IV (AS IV), which has multiple biological functions, on ATO-induced hepatotoxicity and the underlying mechanism. <b><i>Methods:</i></b> ATO treatment induced a rat model of hepatotoxicity, followed by AS IV treatment. Colorimetric kits were used to detect rat liver function indexes including aspartate aminotransferase (AST), alanine transaminase (ALT), malondialdehyde (MDA), and reduced glutathione (GSH). Reactive oxygen species (ROS) level was determined by 2′, 7′-Dichlorodihydrofluorescein diacetate kit. The liver fibrosis and F4/80 expression were detected by Sirius red staining and immunochemistry. Mitochondrial electron transport chain complex I and complex IV activities were examined. The level of mitochondrial membrane potential (MMP) was detected by JC-1 staining. The inflammatory factor levels were detected by quantitative real-time polymerase chain reaction. Western blot detected apoptosis-related proteins and AMPK/SIRT1-related proteins. <b><i>Results:</i></b> ATO increased ALT, AST, MDA, and ROS levels and decreased GSH content but was subsequently reversed by AS IV. AS IV alleviated liver tissue damage caused by ATO. AS IV elevated complex I and complex IV activity and promoted MMP levels in ATO rats. ATO promoted inflammatory factor release in SD rats but was then suppressed by AS IV. AS IV inhibited Bax, cleaved caspase-3 but up-regulated Bcl-2 in ATO-induced rats. ATO inhibited SIRT1 expression and AMPK phosphorylation, which was subsequently promoted by AS IV. <b><i>Conclusion:</i></b> AS IV inhibits ATO-induced hepatotoxicity by activating the AMPK/SIRT1 pathway.

Molecular Mechanisms and Mediators of Hepatotoxicity Resulting from an Excess of Lipids and Non-Alcoholic Fatty Liver Disease

“…If elevations are more than three times the ULN, a second evaluation of the liver function should be carried out [142]. If the high quantities of AST/ALT persist, the statin must be stopped, while switching to another statin or rechallenge may also be possible [143]. Transaminase levels that were overall high and higher than the ULN were present in only 2% of patients receiving statin monotherapy [144].…”

Biased Quantification of Rat Liver Fibrosis—Meta-Analysis with Practical Recommendations and Clinical Implications

“…Mean amount of liver connective tissue in healthy male Sprague-Dawley rats. Graphs (mean ± two standard errors) of the amount of liver connective tissue quantified on histological sections stained with Masson's trichrome[13,14,19,26,29,30,33,38,54,[56][57][58]63] (a) or picrosirius red[4,13,21,25,27,32,34,36,39,[42][43][44][48][49][50]52,55,58,60,62,64] (b) revealed significant differences. Multiple graphs within one study represents multiple rat groups within the study.…”