Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Científicas, Barcelona, Spain.
Cell Death Dis. 2010 Jul 8;1(7):e52. doi: 10.1038/cddis.2010.29.
During partial hepatectomy, ischemia-reperfusion (I/R) is commonly applied in clinical practice to reduce blood flow. Steatotic livers show impaired regenerative response and reduced tolerance to hepatic injury. We examined the effects of tauroursodeoxycholic acid (TUDCA) and 4-phenyl butyric acid (PBA) in steatotic and non-steatotic livers during partial hepatectomy under I/R (PH+I/R). Their effects on the induction of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress were also evaluated. We report that PBA, and especially TUDCA, reduced inflammation, apoptosis and necrosis, and improved liver regeneration in both liver types. Both compounds, especially TUDCA, protected both liver types against ER damage, as they reduced the activation of two of the three pathways of UPR (namely inositol-requiring enzyme and PKR-like ER kinase) and their target molecules caspase 12, c-Jun N-terminal kinase and C/EBP homologous protein-10. Only TUDCA, possibly mediated by extracellular signal-regulated kinase upregulation, inactivated glycogen synthase kinase-3β. This is turn, inactivated mitochondrial voltage-dependent anion channel, reduced cytochrome c release from the mitochondria and caspase 9 activation and protected both liver types against mitochondrial damage. These findings indicate that chemical chaperones, especially TUDCA, could protect steatotic and non-steatotic livers against injury and regeneration failure after PH+I/R.
在部分肝切除术中，常应用缺血再灌注（I/R）以减少血流。脂肪肝显示出受损的再生反应和对肝损伤的耐受性降低。我们研究了牛磺熊脱氧胆酸（TUDCA）和 4-苯丁酸（PBA）在 I/R 下（PH+I/R）的部分肝切除术中在非脂肪性和脂肪性肝脏中的作用。还评估了它们对未折叠蛋白反应（UPR）和内质网（ER）应激诱导的影响。我们报告说，PBA，特别是 TUDCA，减少了两种肝类型的炎症、细胞凋亡和坏死，并改善了肝再生。这两种化合物，特别是 TUDCA，均能保护两种肝类型免受 ER 损伤，因为它们减少了 UPR 的三种途径（即需要肌醇的酶和 PKR 样 ER 激酶）及其靶分子半胱天冬酶 12、c-Jun N 末端激酶和 C/EBP 同源蛋白-10 的激活。只有 TUDCA，可能通过细胞外信号调节激酶的上调来介导，使糖原合酶激酶-3β失活。反过来，失活的线粒体电压依赖性阴离子通道减少了细胞色素 c 从线粒体的释放和半胱天冬酶 9 的激活，并保护两种肝类型免受线粒体损伤。这些发现表明，化学伴侣，特别是 TUDCA，可保护非脂肪性和脂肪性肝脏免受 PH+I/R 后损伤和再生失败的影响。
