Role of Bile Acids in Liver Injury and Regeneration following Acetaminophen Overdose
Role of Bile Acids in Liver Injury and Regeneration following Acetaminophen Overdose
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DOI：
10.1016/j.ajpath.2013.07.012
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发表时间：
2013-11-01
影响因子：
6
通讯作者：
Apte, Udayan
中科院分区：
文献类型：
--
作者：
Bhushan, Bharat;Borude, Prachi;Apte, Udayan
胆汁酸在肝损伤和肝再生中起关键作用，但其在对乙酰氨基酚（APAP）诱导的肝损伤中的作用尚不清楚。我们以C57BL/6小鼠为实验对象，研究了胆汁酸调节对APAP肝毒性的影响。C57BL/6小鼠在给予400 mg/kg APAP治疗前，分别饲喂正常饮食、含有2%胆碱胺（CSA）的饮食或含有0.2%胆酸（CA）的饮食1周。csa介导的胆汁酸耗竭导致APAP治疗后肝损伤显著增加和再生延迟。相比之下，在饮食中添加0.2% CA可适度延缓肝损伤的进展，并显著提高APAP治疗后的肝脏再生。在APAP治疗后，csa介导的胆囊酸消耗或CA补充均不影响肝脏CYP2E1水平或谷胱甘肽消耗。APAP处理后，csa喂养小鼠的c-Jun n端蛋白激酶活性显著升高，肠成纤维细胞生长因子15 mRNA水平显著降低。相比之下，饲粮添加0.2% CA的小鼠肠道c-Jun n端蛋白激酶活性显著降低，成纤维细胞生长因子15 mRNA含量提高12倍。在快速诱导细胞周期蛋白D1后给药APAP的CA日粮小鼠肝再生明显加快。综上所述，这些数据表明胆汁酸在apap诱导的肝损伤的开始和恢复中都起着关键作用。
Bile acids play a critical role in Liver injury and regeneration, but their role in acetaminophen (APAP)-induced Liver injury is not known. We tested the effect of bile acid modulation on APAP hepatotoxicity using C57BL/6 mice, which were fed a normal diet, a 2% choleslyramine (CSA)-containing diet for bile acid depletion, or a 0.2% cholic acid (CA)-containing diet for 1 week before treatment with 400 mg/kg APAP. CSA-mediated bile acid depletion resulted in significantly higher Liver injury and delayed regeneration after APAP treatment. In contrast, 0.2% CA supplementation in the diet resulted in a moderate delay in progression of Liver injury and significantly higher Liver regeneration after APAP treatment. Either CSA-mediated bile acid depletion or CA supplementation did not affect hepatic CYP2E1 levels or glutathione depletion after APAP treatment. CSA-fed mice exhibited significantly higher activation of c-Jun N-terminal protein kinases and a significant decrease in intestinal fibroblast growth factor 15 mRNA after APAP treatment. In contrast, mice fed a 0.2% CA diet had significantly lower c-Jun N-terminal protein kinase activation and 12-fold higher fibroblast growth factor 15 mRNA in the intestines. Liver regeneration after APAP treatment was significantly faster in CA diet fed mice after APAP administration secondary to rapid cyclin D1 induction. Taken together, these data indicate that bile acids play a critical role in both initiation and recovery of APAP-induced Liver injury.