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标题：Molecular Mechanisms for Protection of Hepatocytes against Bile Salt Cytotoxicity
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作者：Shin-ya Morita ; Yoshito Ikeda ; Tokuji Tsuji 等
期刊名称：Chemical and Pharmaceutical Bulletin
印刷版ISSN：0009-2363
电子版ISSN：1347-5223
出版年度：2019
卷号：67
期号：4
页码：333-340
DOI：10.1248/cpb.c18-01029
出版社：The Pharmaceutical Society of Japan
摘要：Biliary lipids consist mainly of bile salts, phospholipids and cholesterol, which form mixed micelles and vesicles. Bile salts play various physiological roles but have damaging effects on cell membranes due to their detergent properties. The cytotoxicity of bile salts on hepatocytes leads to liver injuries and is largely determined by the bile salt species, the concentrations of bile salts, phospholipids and cholesterol, and the lipid composition of cell membranes. In bile, monomers and simple micelles of bile salts coexist with mixed micelles and vesicles in dynamic equilibrium, and contribute to the cytotoxicity on hepatocytes. The ATP-binding cassette (ABC) transporter family members, ABCB11, ABCB4 and ABCG5/ABCG8, mediate the biliary secretion of bile salts, phospholipids and cholesterol, respectively. Mutations in ABCB4 result in severe cholestatic diseases, and the biliary phospholipids are necessary for the attenuation of bile salt cytotoxicity. On the other hand, cholesterol reverses the cytoprotective effects of phospholipids against bile salts. In addition, phosphatidylethanolamine N -methyltransferase increases the cell resistance to bile salts by changing the phospholipid composition and structures of the apical membranes. In this review, we focus on the molecular mechanisms for the protection of hepatocytes against bile salt cytotoxicity. Further understanding of these mechanisms will help to develop new therapeutic strategies for cholestatic liver diseases.
关键词：bile salt;phospholipid;cholesterol;ATP-binding cassette transporter B4 (ABCB4);phosphatidylethanolamine N-methyltransferase;cytotoxicity