Yuhui Yan , Wenyu Wang , Aiwen Yan , Haonan Zhu , Qiang Meng
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引用次数: 0
Abstract
Cholestasis, a condition marked by bile acid accumulation in the liver and body systems, leads to liver dysfunction and cirrhosis. Currently, ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are the only two FDA-approved drugs for Cholestasis. Thus, new therapeutic approaches need to be developed. In this study, we validated the liver-protective properties of β-sitosterol (SIT), a key bioactive element abundant in plants, against hepatic toxicity and cholestasis induced by alpha-naphthylisothiocyanate(ANIT), while elucidating its mechanisms of action both in vivo and in vitro. SIT's FXR activation was confirmed via molecular docking and dual-luciferase assays. In the mechanisms of SIT hepatoprotection, the expression levels of bile salt export pump (Bsep) and multidrug resistance protein2 (Mrp2) which are bile acid efflux transporter, and sulfate transferase 2a1 (Sult2a1) which is a bile acid metabolizing enzyme were all increased by SIT, whereas the expression of uptake transporter sodium taurocholate transporting polypeptide (Ntcp), bile acid synthesis enzyme cholesterol 7α-hydroxylase (Cyp7a1) and oxysterol 12α-hydroxylase (Cyp8b1) was decreased by SIT. In addition, SIT alleviated liver inflammation by suppressing inflammatory factor expression. However, FXR antagonist guggulsterone and FXR siRNA abolished SIT's improvements in liver histology, bile acid transporters, and enzymes. Conclusively, through activating FXR, SIT provides a protective effect against hepatotoxicity and cholestasis. SIT might serve as a new potential therapeutic strategy for the treatment of cholestatic liver diseases.
期刊介绍：
Toxicology in Vitro publishes original research papers and reviews on the application and use of in vitro systems for assessing or predicting the toxic effects of chemicals and elucidating their mechanisms of action. These in vitro techniques include utilizing cell or tissue cultures, isolated cells, tissue slices, subcellular fractions, transgenic cell cultures, and cells from transgenic organisms, as well as in silico modelling. The Journal will focus on investigations that involve the development and validation of new in vitro methods, e.g. for prediction of toxic effects based on traditional and in silico modelling; on the use of methods in high-throughput toxicology and pharmacology; elucidation of mechanisms of toxic action; the application of genomics, transcriptomics and proteomics in toxicology, as well as on comparative studies that characterise the relationship between in vitro and in vivo findings. The Journal strongly encourages the submission of manuscripts that focus on the development of in vitro methods, their practical applications and regulatory use (e.g. in the areas of food components cosmetics, pharmaceuticals, pesticides, and industrial chemicals). Toxicology in Vitro discourages papers that record reporting on toxicological effects from materials, such as plant extracts or herbal medicines, that have not been chemically characterized.
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