Spontaneous liver fibrosis induced by long term dietary vitamin D deficiency in adult mice is related to chronic inflammation and enhanced apoptosis.
Spontaneous liver fibrosis induced by long term dietary vitamin D deficiency in adult mice is related to chronic inflammation and enhanced apoptosis.
复制标题
DOI：
10.1139/cjpp-2014-0275
复制
发表时间：
2015-03
影响因子：
2.1
通讯作者：
Longdong Zhu;M. Kong;Yuanping Han;L. Bai;Xiaohui Zhang;Yu Chen;S. Zheng;Hong Yuan;Z. Duan
中科院分区：
文献类型：
--
作者：
Longdong Zhu;M. Kong;Yuanping Han;L. Bai;Xiaohui Zhang;Yu Chen;S. Zheng;Hong Yuan;Z. Duan
流行病学研究显示，维生素D缺乏与各种慢性肝病有关。然而，目前尚不清楚缺乏维生素D是否会在动物模型中导致自发性肝纤维化。为了研究这一点，小鼠被喂以对照饮食或缺乏维生素D的饮食(VDD饮食)。以四氯化碳诱导大鼠肝纤维化为阳性对照。在这里，我们第一次显示，在喂食VDD饮食的小鼠中，肝纤维化自发发展。长期服用VDD饮食会导致坏死性炎症和肝纤维化。肿瘤坏死因子-α、白介素1、白介素6、Toll样受体4和单核细胞趋化蛋白-1等炎症介质在饲喂VDD饲料的小鼠肝脏中表达上调。相反，服用VDD饮食的小鼠肝脏中Th2/M2标志物如IL-10、IL-13、精氨酸酶1和血红素加氧酶-1的表达下调。在喂食维生素D饮食的小鼠的肝脏中，诱导了转化生长因子-β-1和基质金属蛋白酶13，它们是肝纤维化的重要因素。此外，VDD饮食引起实质细胞凋亡，与Fas和FasL水平升高一致，并降低了Bcl2和Bclx的水平。因此，长期缺乏维生素D会引发慢性炎症，从而诱导肝脏细胞凋亡，从而激活肝星状细胞，启动肝纤维化。
Epidemiological studies have revealed an association between vitamin D deficiency and various chronic liver diseases. However, it is not known whether lack of vitamin D can induce spontaneous liver fibrosis in an animal model. To study this, mice were fed either a control diet or a vitamin D deficient diet (VDD diet). For the positive control, liver fibrosis was induced with carbon tetrachloride. Here we show, for the first time, that liver fibrosis spontaneously developed in mice fed the VDD diet. Long-term administration of a VDD diet resulted in necro-inflammation and liver fibrosis. Inflammatory mediators including tumor necrosis factor-α, interleulin-1, interleukin-6, Toll-like-receptor 4, and monocyte chemotactic protein-1 were up-regulated in the livers of the mice fed the VDD diet. Conversely, the expression of Th2/M2 markers such as IL-10, IL-13, arginase 1, and heme oxygenase-1 were down-regulated in the livers of mice fed the VDD diet. Transforming growth factor-β1 and matrix metalloproteinase 13, which are important for fibrosis, were induced in the livers of mice fed the VDD diet. Moreover, the VDD diet triggered apoptosis in the parenchymal cells, in agreement with the increased levels of Fas and FasL, and decreased Bcl2 and Bclx. Thus, long-term vitamin D deficiency can provoke chronic inflammation that can induce liver apoptosis, which consequently activates hepatic stellate cells to initiate liver fibrosis.