Several studies have characterized the cellular and molecular mechanisms of hepatocyte injury caused by the retention of hydrophobic bile acids （BAs） in cholestatic diseases. BAs may disrupt cell membranes through t...Several studies have characterized the cellular and molecular mechanisms of hepatocyte injury caused by the retention of hydrophobic bile acids （BAs） in cholestatic diseases. BAs may disrupt cell membranes through their detergent action on lipid components and can promote the generation of reactive oxygen species that, in turn, oxidatively modify lipids, proteins, and nucleic acids, and eventually cause hepatocyte necrosis and apoptosis. Several pathways are involved in triggering hepatocyte apoptosis. Toxic BAs can activate hepatocyte death receptors directly and induce oxidative damage, thereby causing mitochondrial dysfunction, and induce endoplasmic reticulum stress. When these compounds are taken up and accumulate inside biliary cells, they can also cause apoptosis. Regarding extrahepatic tissues, the accumulation of BAs in the systemic circulation may contribute to endothelial injury in the kidney and lungs. In gastrointestinal cells, BAs may behave as cancer promoters through an indirect mechanism involving oxidative stress and DNA damage, as well as acting as selection agents for apoptosis-resistant cells. The accumulation of BAs may have also deleterious effects on placental and fetal cells. However, other BAs, such as ursodeoxycholic acid, have been shown to modulate BA-induced injury in hepatocytes. The major beneficial effects of treatment with ursodeoxycholic acid are protection against cytotoxicity due to more toxic BAs; the stimulation of hepatobiliary secretion; antioxidant activity, due in part to an enhancement in glutathione levels; and the inhibition of liver cell apoptosis. Other natural BAs or their derivatives, such as cholyI-N- methylglycine or pharmacological properties. cholylsarcosine, interest owing have also aroused to their protective展开更多
基金Supported by Instituto de Salud CarlosTM,FIS, Spain (GrantsPI070517 and PI080151)Fundacion Investigacion Medica Mutua Madrilea, Spain (Conv-TM,, 2006)+3 种基金Junta de Castillay Leon, Spain (Grants GR75-2008, SA033A08, SA03508 and SA03608)Ministerio de Ciencia y Tecnologia, Plan Nacional de Investigacion Cientifi ca, Desarrollo e Innovacion Tecnologica, Spain (Grant BFU2006-12577)The group is member of the Network for Cooperative Research on Membrane Transport Proteins (REIT), co-funded by the Ministerio de Educacion y Ciencia, Spain, and the European Regional Development Fund (ERDF) (Grant BFU2007-30688-E/BFI)belongs to the CIBERehd (Centro de Investigacion Biomedica en Red para el Estudio de Enfermedades Hepaticas y Digestivas), Instituto de Salud CarlosTM
文摘Several studies have characterized the cellular and molecular mechanisms of hepatocyte injury caused by the retention of hydrophobic bile acids （BAs） in cholestatic diseases. BAs may disrupt cell membranes through their detergent action on lipid components and can promote the generation of reactive oxygen species that, in turn, oxidatively modify lipids, proteins, and nucleic acids, and eventually cause hepatocyte necrosis and apoptosis. Several pathways are involved in triggering hepatocyte apoptosis. Toxic BAs can activate hepatocyte death receptors directly and induce oxidative damage, thereby causing mitochondrial dysfunction, and induce endoplasmic reticulum stress. When these compounds are taken up and accumulate inside biliary cells, they can also cause apoptosis. Regarding extrahepatic tissues, the accumulation of BAs in the systemic circulation may contribute to endothelial injury in the kidney and lungs. In gastrointestinal cells, BAs may behave as cancer promoters through an indirect mechanism involving oxidative stress and DNA damage, as well as acting as selection agents for apoptosis-resistant cells. The accumulation of BAs may have also deleterious effects on placental and fetal cells. However, other BAs, such as ursodeoxycholic acid, have been shown to modulate BA-induced injury in hepatocytes. The major beneficial effects of treatment with ursodeoxycholic acid are protection against cytotoxicity due to more toxic BAs; the stimulation of hepatobiliary secretion; antioxidant activity, due in part to an enhancement in glutathione levels; and the inhibition of liver cell apoptosis. Other natural BAs or their derivatives, such as cholyI-N- methylglycine or pharmacological properties. cholylsarcosine, interest owing have also aroused to their protective
