Lumican, an extracellular matrix proteoglycan, is a novel requisite for hepatic fibrosis.
Lumican, an extracellular matrix proteoglycan, is a novel requisite for hepatic fibrosis.
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DOI：
10.1038/labinvest.2012.121
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发表时间：
2012-12
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中科院分区：
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Lumcan是一种细胞外基质蛋白多糖，先前被证明随着非酒精性脂肪性肝炎(NASH)病情的加重而上调。虽然LUMICAN参与了肝外组织中胶原纤维的形成，但对LUMICAN在肝脏疾病中的作用知之甚少。因此，我们确定了LUMICA在非临床NASH的病因中的表达。我们的结果表明，鲁米肯在丙型肝炎病毒感染的临床标本、慢性和急性肝损伤的实验性啮齿动物模型中表达上调，并可在体外被促纤维化细胞因子转化生长因子β1(转化生长因子β1)和脂毒性棕榈酸诱导。综上所述，这些结果提示鲁米肯在肝纤维化中的作用。为了研究LUMICAN在肝纤维化中的功能作用，将LUMICAN空(Null)和野生型(WT)产仔鼠分别经腹腔注射四氯化碳。分析血清和肝组织的肝损伤、纤维化、基质转换和增殖指标。空白组大鼠肝纤维化显著减轻(p<；0.05)。矛盾的是，转化生长因子β1和胶原1等纤维化相关基因的基因表达在空白动物中数值较高，而在WT动物中统计上并不显著。另一方面，α平滑肌肌动蛋白表达(α-SMA)是激活的成纤维细胞的标志，它是胶原产生的主要贡献者，在空白动物中显著高于WT仔猪(p<；0.05)。在基质金属蛋白酶中，MMP13在空白组显著升高(p<0.05)。超微结构成像显示，Null和WT小鼠肝脏胶原纤维的组织和空间分布存在差异。空白组细胞增殖显著增强(p<；0.05)。我们得出结论，鲁米肯是肝纤维化的先决条件。鲁米肯缺乏在肝纤维化中的保护作用似乎是在胶原生成的下游，并通过胶原纤维形成受损、基质周转增加和增殖反应增强的综合作用来调节。
Lumican, an extracellular matrix proteoglycan was previously shown to be upregulated with increasing severity of nonalcoholic steatohepatitis (NASH). Although lumican is involved in collagen fibrillogenesis in extra-hepatic tissues, little is known about the role of lumican in hepatic disease. We therefore determined lumican expression in etiologies other than clinical NASH. Our results indicated that lumican is upregulated in clinical samples of hepatitis C virus infection, in experimental rodent models of chronic and acute liver injury and could additionally be induced in vitro in response to the pro-fibrotic cytokine transforming growth factorβ1 (TGFβ 1) and to lipotoxic palmitic acid. Together, these results suggested a role for lumican in hepatic fibrosis. To investigate the functional role of lumican in hepatic fibrosis, lumican null (Null) and wild-type (WT) littermates were administered carbon tetrachloride intra-peritoneally. Serum and liver tissue were analyzed for indices of liver injury, fibrosis, matrix turnover, and proliferation. Hepatic fibrosis was greatly reduced in null animals (p<0.05). Paradoxically, gene expression of fibrosis-related genes such as TGFβ 1 and collagen 1 was numerically higher in null animals though statistically insignificant from WT animals. On the other hand, αsmooth muscle actin expression (α-SMA), a marker for activated fibroblasts, the main contributors of collagen production was significantly higher (p<0.05) in null animals as compared with WT littermates. Among the matrix metalloproteases (MMP), MMP13 was significantly increased (p<0.05) in null animals. Ultra-structural imaging indicated differences in the organization and spatial distribution of hepatic collagen fibrils of null and WT mice. Cell proliferation was significantly increased (p<0.05) in null animals. We conclude that lumican is a prerequisite for hepatic fibrosis. The protective effect of lumican deficiency in hepatic fibrosis appears to be downstream of collagen production and mediated through the combined effects of impaired collagen fibrillogenesis, increased matrix turnover, and an enhanced proliferative response.
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