Chen Weina, Han Chang, Zhang Jinqiang, Song Kyoungsub, Wang Ying, Wu Tong
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana; Department of Gastroenterology and Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Am J Pathol. 2015 Apr;185(4):1033-44. doi: 10.1016/j.ajpath.2014.12.020.
Fas-induced apoptosis is involved in diverse liver diseases. Herein, we investigated the effect of Mir155 deletion on Fas-induced liver injury. Wild-type (WT) mice and Mir155 knockout (KO) mice were i.p. administered with the anti-Fas antibody (Jo2) to determine animal survival and the extent of liver injury. After Jo2 injection, the Mir155 KO mice exhibited prolonged survival versus the WT mice (P < 0.01). The Mir155 KO mice showed lower alanine aminotransferase and aspartate aminotransferase levels, less liver tissue damage, fewer apoptotic hepatocytes, and lower liver tissue caspase 3/7, 8, and 9 activities compared with the WT mice, indicating that Mir155 deletion prevents Fas-induced hepatocyte apoptosis and liver injury. Hepatocytes isolated from Mir155 KO mice also showed resistance to Fas-induced apoptosis, in vitro. Higher protein level of myeloid cell leukemia-1 (Mcl-1) was also observed in Mir155 KO hepatocytes compared to WT hepatocytes. A miR-155 binding site was identified in the 3'-untranslated region of Mcl-1 mRNA; Mcl1 was identified as a direct target of miR-155 in hepatocytes. Consistently, pretreatment with a siRNA specific for Mcl1 reversed Mir155 deletion-mediated protection against Jo2-induced liver tissue damage. Finally, restoration of Mir155 expression in Mir155 KO mice abolished the protection against Fas-induced hepatocyte apoptosis. Taken together, these findings demonstrate that deletion of Mir155 prevents Fas-induced hepatocyte apoptosis and liver injury through the up-regulation of Mcl1.
Fas 诱导的细胞凋亡参与多种肝脏疾病。在此，我们研究了 Mir155 缺失对 Fas 诱导的肝损伤的影响。将野生型（WT）小鼠和 Mir155 基因敲除（KO）小鼠腹腔注射抗 Fas 抗体（Jo2），以确定动物存活率和肝损伤程度。注射 Jo2 后，与 WT 小鼠相比，Mir155 KO 小鼠存活时间延长（P < 0.01）。与 WT 小鼠相比，Mir155 KO 小鼠的丙氨酸转氨酶和天冬氨酸转氨酶水平较低，肝组织损伤较轻，凋亡肝细胞较少，肝组织 caspase 3/7、8 和 9 的活性较低，表明 Mir155 缺失可预防 Fas 诱导的肝细胞凋亡和肝损伤。体外实验中，从 Mir155 KO 小鼠分离的肝细胞也显示出对 Fas 诱导的细胞凋亡具有抗性。与 WT 肝细胞相比，在 Mir155 KO 肝细胞中还观察到髓样细胞白血病-1（Mcl-1）蛋白水平较高。在 Mcl-1 mRNA 的 3'非翻译区鉴定出一个 miR-155 结合位点；Mcl1 被确定为肝细胞中 miR-155 的直接靶点。一致的是，用针对 Mcl1 的 siRNA 预处理可逆转 Mir155 缺失介导的对 Jo2 诱导的肝组织损伤的保护作用。最后，在 Mir155 KO 小鼠中恢复 Mir155 的表达消除了对 Fas 诱导的肝细胞凋亡的保护作用。综上所述，这些发现表明 Mir155 的缺失通过上调 Mcl1 来预防 Fas 诱导的肝细胞凋亡和肝损伤。
