Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin
Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin
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DOI：
10.1053/j.gastro.2003.08.029
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发表时间：
2003-12-01
期刊：
影响因子：
29.4
通讯作者：
Matsuzawa, Y
中科院分区：
文献类型：
--
作者：
Kamada, Y;Tamura, S;Matsuzawa, Y
背景与目的：肥胖是肝纤维化的危险因素之一，肥胖时血浆脂联素水平降低。肝星状细胞在肝纤维化中起重要作用。当它们被激活时，它们会转化为肌纤维母细胞样细胞。脂联素抑制血管平滑肌细胞的增殖和迁移，其特性与肝星状细胞相似。脂联素在肝纤维化中可能具有生物学意义。研究方法：通过使用脂联素基因敲除小鼠和腺病毒介导的脂联素表达系统，检测脂联素对四氯化碳每周两次共12周诱导的肝纤维化的作用。我们还研究了脂联素在活化的肝星状细胞中的作用。结果如下：当小鼠每周两次给予四氯化碳（300穆尔/kg体重）持续12周时，基因敲除小鼠显示出广泛的肝纤维化，与野生型小鼠相比，转化生长因子-β 1和结缔组织生长因子的表达增强（P < 0.05）。在四氯化碳（1000穆尔/kg体重）治疗前注射产生脂联素的腺病毒（AdADN）可预防野生型小鼠的肝纤维化（P < 0.001）。在第6周注射AdADN可减轻肝纤维化，即使再给予四氯化碳6周（共12周）。在培养的肝星状细胞中，脂联素抑制血小板源性生长因子诱导的增殖和迁移，并减弱转化生长因子-β 1对转化生长因子-β 1和结缔组织生长因子的基因表达以及Smad 2核转位的影响。结论：脂联素具有减轻肝纤维化的作用，可能成为防治肝纤维化的新途径。
Background & Aims: Obesity is one of the risk factors for liver fibrosis, in which plasma adiponectin, an adipocytokine, levels are decreased. Hepatic stellate cells play central roles in liver fibrosis. When they are activated, they undergo transformation to myofibroblast-like cells. Adiponectin suppresses the proliferation and migration of vascular smooth muscle cells, whose characteristics are similar to those of hepatic stellate cells. Adiponectin could have biological significances in liver fibrosis. Methods: The role of adiponectin on liver fibrosis induced by the administration of carbon tetrachloride twice a week for 12 weeks was tested by using adiponectin-knockout mice and an adenovirus-mediated adiponectin-expression system. We also investigated the effect of adiponectin in activated hepatic stellate cells. Results: When mice were administered carbon tetrachloride (300 muL/kg body weight) twice a week for 12 weeks, knockout mice showed extensive liver fibrosis with an enhanced expression of transforming growth factor-beta1 and connective tissue growth factor compared with wild-type mice (P < 0.05). Injection of adenovirus producing adiponectin (AdADN) before carbon tetrachloride (1000 muL/kg body weight) treatment prevented liver fibrosis in wild-type mice (P < 0.001). Injection of AdADN at 6 weeks attenuated liver fibrosis even though carbon tetrachloride was given for an additional 6 weeks (total of 12 weeks). In cultured hepatic stellate cells, adiponectin suppressed platelet-derived growth factor-induced proliferation and migration and attenuated the effect of transforming growth factor-beta1 on the gene expression of transforming growth factor-beta1 and connective tissue growth factor and on nuclear translocation of Smad2. Conclusions: The findings indicate that adiponectin attenuates liver fibrosis and could be a novel approach in its prevention.