Fibromodulin, an oxidative stress-sensitive proteoglycan, regulates the fibrogenic response to liver injury in mice.
Fibromodulin, an oxidative stress-sensitive proteoglycan, regulates the fibrogenic response to liver injury in mice.
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DOI：
10.1053/j.gastro.2011.11.029
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发表时间：
2012-03
期刊：
影响因子：
29.4
通讯作者：
Nieto N
中科院分区：
文献类型：
--
作者：
Mormone E;Lu Y;Ge X;Fiel MI;Nieto N
胶原蛋白I沉积有助于肝纤维化，但对介导这一过程的其他因素知之甚少。纤调素是一种肝脏蛋白多糖，调节细胞外基质组织，并由纤维化刺激诱导。我们认为纤调蛋白通过调节肝星状细胞（HSC）的纤维化表型而参与纤维化的发病机制。我们分析了丙型肝炎相关肝硬化患者和健康个体（对照）的肝脏样本。我们使用共培养模型来研究大鼠HSC、肝细胞和肝窦内皮细胞之间的相互作用。我们通过胆管结扎、注射CCl 4或给予硫代乙酰胺诱导野生型和Fmod−/−小鼠的肝脏纤维化。肝硬化患者的肝脏样本中纤维调节蛋白信使RNA和蛋白质的水平高于对照组。胆管结扎、四氯化碳和硫代乙酰胺均增加了野生型小鼠的纤调蛋白水平。肝星状细胞、肝细胞和肝窦内皮细胞产生并分泌纤维调节素。用表达纤调蛋白的腺病毒感染HSC增加了I型胶原和α-平滑肌肌动蛋白的表达，表明HSC的活化和纤维化潜能增加。重组纤调素促进HSC的增殖、迁移和侵袭，有助于其纤维化活性。纤调素对活性氧敏感。表达细胞色素P450 2 E1的HepG 2细胞产生纤调蛋白，HSC响应于促氧化剂增加纤调蛋白的产生。在小鼠中，抗氧化剂的施用防止了响应于CCl 4的纤调蛋白的增加。肝细胞或肝窦内皮细胞与HSC共培养增加了培养基中活性氧的水平，沿着胶原蛋白I和纤调蛋白;过氧化氢酶阻止了这种增加。纤调素结合胶原蛋白I，但结合并没有阻止胶原蛋白I降解基质金属蛋白酶13。胆管结扎导致野生型小鼠肝纤维化，但Fmod−/−小鼠没有。肝硬化患者肝脏中纤维调节蛋白水平升高。肝纤维调节蛋白激活HSC并促进胶原I沉积，这导致小鼠肝纤维化。
Collagen I deposition contributes to liver fibrosis, yet little is known about other factors that mediate this process. Fibromodulin is a liver proteoglycan that regulates extracellular matrix organization and is induced by fibrogenic stimuli. We propose that fibromodulin contributes to the pathogenesis of fibrosis by regulating the fibrogenic phenotype of hepatic stellate cells (HSCs). We analyzed liver samples from patients with hepatitis C–associated cirrhosis and healthy individuals (controls). We used a coculture model to study interactions among rat HSCs, hepatocytes, and sinusoidal endothelial cells. We induced fibrosis in livers of wild-type and Fmod−/− mice by bile duct ligation, injection of CCl4, or administration of thioacetamide. Liver samples from patients with cirrhosis had higher levels of fibromodulin messenger RNA and protein than controls. Bile duct ligation, CCl4, and thioacetamide each increased levels of fibromodulin protein in wild-type mice. HSCs, hepatocytes, and sinusoidal endothelial cells produced and secreted fibromodulin. Infection of HSCs with an adenovirus that expressed fibromodulin increased expression of collagen I and α–smooth muscle actin, indicating increased activation of HSCs and fibrogenic potential. Recombinant fibromodulin promoted proliferation, migration, and invasion of HSCs, contributing to their fibrogenic activity. Fibromodulin was sensitive to reactive oxygen species. HepG2 cells that express cytochrome P450 2E1 produced fibromodulin, and HSCs increased fibromodulin production in response to pro-oxidants. In mice, administration of an antioxidant prevented the increase in fibromodulin in response to CCl4. Coculture of hepatocytes or sinusoidal endothelial cells with HSCs increased the levels of reactive oxygen species in the culture medium, along with collagen I and fibromodulin proteins; this increase was prevented by catalase. Fibromodulin bound to collagen I, but the binding did not prevent collagen I degradation by matrix metalloproteinase 13. Bile duct ligation caused liver fibrosis in wild-type but not Fmod−/− mice. Fibromodulin levels are increased in livers of patients with cirrhosis. Hepatic fibromodulin activates HSCs and promotes collagen I deposition, which leads to liver fibrosis in mice.
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影响因子：
3.2
作者：
Goldberg, M;Septier, D;Ameye, LG
通讯作者：
Ameye, LG
DOI：
10.1042/bss0700115
发表时间：
2003-01-01
期刊：
PROTEASES AND THE REGULATION OF BIOLOGICAL PROCESSES
影响因子：
--
作者：
Poole, AR;Nelson, F;Billinghurst, RC
通讯作者：
Billinghurst, RC
影响因子：
13.5
作者：
Nieto, Natalia
通讯作者：
Nieto, Natalia
影响因子：
4.8
作者：
Nieto, N;Cederbaum, AI
通讯作者：
Cederbaum, AI
影响因子：
7.8
作者：
Chakravarti, S;Magnuson, T;Lass, JH;Jepsen, KJ;LaMantia, C;Carroll, H
通讯作者：
Carroll, H