Department of Infectious Disease, Rui jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China.
World J Gastroenterol. 2013 Jul 28;19(28):4475-85. doi: 10.3748/wjg.v19.i28.4475.
To describe the role of resistin in liver fibrosis.
For the in vivo animal study, Sprague Dawley rats were subjected to bile duct ligation (BDL) for 4 wk. Rat liver, adipose tissue (epididymal fat) and serum were analyzed for resistin expression. For the in vitro experiment, rat primary hepatic stellate cells (HSCs) and Kupffer cells (KCs) were used. HSCs were exposed to recombinant resistin, and collagen I, transforming growth factor β1, α smooth muscle actin, tissue inhibitor of metalloproteinase 1 and connective tissue growth factor expression were analyzed. Resistin gene and protein expression was quantified as was the expression of pro-inflammatory cytokines including tumor necrosis factor α (TNFα), interleukin (IL)-1, IL-6, IL-8 and monocyte chemotactic protein-1 (MCP-1). The effects of resistin on HSC proliferation, migration and apoptosis were determined. The effects of resistin on KCs were also investigated.
Following BDL, rat epididymal fat and serum rather than liver showed higher resistin expression compared to control rats. In liver, resistin was expressed in quiescent HSCs and KCs. Resistin treatment resulted in enhancement of TNFα, IL-6, IL-8 and MCP-1 gene expression and increased IL-6 and MCP-1 protein in HSCs. Resistin activated HSC phospho-MAPK/p38, and p38 inhibition diminished IL-6 and MCP-1 expression. Furthermore, resistin facilitated HSC proliferation and migration, but decreased apoptosis which was via an IL-6 and MCP-1 mechanism. Finally, resistin-induced transforming growth factor β1 from KCs enhanced HSC collagen I expression.
Resistin directly and indirectly modulates HSC behavior towards a more pro-fibrogenic phenotype.
描述抵抗素在肝纤维化中的作用。
在体内动物研究中，将 Sprague Dawley 大鼠进行胆管结扎（BDL）4 周。分析大鼠肝、脂肪组织（附睾脂肪）和血清中的抵抗素表达。在体外实验中，使用大鼠原代肝星状细胞（HSCs）和枯否细胞（KCs）。将 HSCs 暴露于重组抵抗素中，分析胶原 I、转化生长因子 β1、α平滑肌肌动蛋白、组织金属蛋白酶抑制剂 1 和结缔组织生长因子的表达。定量分析抵抗素基因和蛋白表达以及促炎细胞因子（包括肿瘤坏死因子 α（TNFα）、白细胞介素（IL）-1、IL-6、IL-8 和单核细胞趋化蛋白 1（MCP-1））的表达。确定抵抗素对 HSC 增殖、迁移和凋亡的影响。还研究了抵抗素对 KCs 的影响。
BDL 后，与对照大鼠相比，大鼠附睾脂肪和血清而不是肝脏显示出更高的抵抗素表达。在肝脏中，静止的 HSCs 和 KCs 表达抵抗素。抵抗素处理导致 TNFα、IL-6、IL-8 和 MCP-1 基因表达增强，并增加 HSCs 中 IL-6 和 MCP-1 蛋白。抵抗素激活 HSC 磷酸化 MAPK/p38，而 p38 抑制减少了 IL-6 和 MCP-1 的表达。此外，抵抗素促进 HSC 的增殖和迁移，但减少了凋亡，这是通过 IL-6 和 MCP-1 机制实现的。最后，抵抗素诱导的 KCs 转化生长因子 β1 增强了 HSC 胶原 I 的表达。
抵抗素直接和间接调节 HSC 行为，使其向更具纤维生成表型的方向发展。
