Xin Guangda, Qin Shaoyou, Wang Song, Wang Xu, Zhang Yonggui, Wang Jiangbin
Department of Nephrology, China-Japan Union Hospital of Jilin University, Changchun 130033, PR China.
Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun 130033, PR China.
Exp Biol Med (Maywood). 2015 Oct;240(10):1279-86. doi: 10.1177/1535370215570189. Epub 2015 Mar 18.
Recent research has shown that the occurrence of gender disparity in liver cancer associated with sex differences in MyD88-dependent IL-6 production, but the role of this signaling pathway in sex differences of non-alcoholic steatohepatitis (NASH) remains unknown. To investigate the effects of sex hormone-specific intervention on pathology and progression of NASH, and on the inflammatory TLR-MyD88-IL-6 signaling pathway NASH was modeled in C57/BL6 mice by feeding a methionine and choline-deficient (MCD) diet for 4 weeks. Male mice were subjected to sex hormone-related interventions such as orchidectomy, and orchidectomy combined with administration of either testosterone propionate or estradiol benzoate. Next, the degree of non-alcoholic fatty liver disease activity score (NAS), serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and the expression level of MyD88 and IL-6, were compared between these groups. Males developed more serious inflammatory problems and had a higher NAS than the females. Sex-specific intervention in male mice by orchidectomy reduced NAS, ALT, and AST, and the expression level of MyD88 and IL-6. But administration of exogenous androgen had no influence on either NAS or the expression of ALT, AST, MyD88, and IL-6. On the other hand, exogenous estrogen could alleviate the pathological damage caused by NASH, as well as reduce NAS, ALT and AST, and the expression of MyD88 and IL-6. The result show different sex hormone-related interventions affected the severity of NASH, possibly by modulating the level of sex hormones and regulating the TLR-MyD88-IL-6 signaling pathway.
近期研究表明，肝癌中性别差异的发生与依赖髓样分化因子88（MyD88）的白细胞介素-6（IL-6）产生的性别差异有关，但该信号通路在非酒精性脂肪性肝炎（NASH）性别差异中的作用尚不清楚。为了研究性激素特异性干预对NASH病理和进展以及对炎性Toll样受体（TLR）-MyD88-IL-6信号通路的影响，通过给C57/BL6小鼠喂食蛋氨酸和胆碱缺乏（MCD）饮食4周来建立NASH模型。对雄性小鼠进行与性激素相关的干预，如睾丸切除术，以及睾丸切除术联合丙酸睾酮或苯甲酸雌二醇给药。接下来，比较这些组之间的非酒精性脂肪性肝病活动评分（NAS）程度、血清丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）水平，以及MyD88和IL-6的表达水平。雄性比雌性出现更严重的炎症问题且NAS更高。通过睾丸切除术对雄性小鼠进行性别特异性干预可降低NAS、ALT和AST，以及MyD88和IL-6的表达水平。但外源性雄激素给药对NAS或ALT、AST、MyD88和IL-6的表达均无影响。另一方面，外源性雌激素可减轻NASH引起的病理损伤，以及降低NAS、ALT和AST，以及MyD88和IL-6的表达。结果表明，不同的性激素相关干预可能通过调节性激素水平和调控TLR-MyD88-IL-信号通路来影响NASH的严重程度。
