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Cell Research:肝细胞中HNF1α的调控机制

摘要 : 第二军医大学的研究团队发现,HNF1α调控的反馈回路通过肝细胞和肝星状细胞的互作对肝纤维化过程进行调控。这项研究发表在七月十四日的Cell Research杂志上,文章的通讯作者是第二军医大学的张俊平(Jun-Ping Zhang)教授和谢渭芬(Wei-Fen Xie)教授。

 肝纤维化(hepatic fibrosis)是肝损伤后的修复反应,许多慢性肝病到晚期都会发生这样的组织学变化,涉及一系列复杂的细胞及分子机制。肝细胞在肝脏内稳态的维持中非常关键,但人们并不清楚肝细胞在肝纤维化中扮演了怎样的角色。

肝细胞核因子1α(HNF1α)是在肝脏中含量丰富的转录因子,对于肝细胞的功能很重要。第二军医大学的研究团队发现,HNF1α调控的反馈回路通过肝细胞和肝星状细胞的互作对肝纤维化过程进行调控。这项研究发表在七月十四日的Cell Research杂志上,文章的通讯作者是第二军医大学的张俊平(Jun-Ping Zhang)教授和谢渭芬(Wei-Fen Xie)教授。

研究显示,在人类和大鼠的纤维化肝脏中,HNF1α的表达受到了显著压制。敲低肝脏中的HNF1α会大大加重肝纤维化,而强制表达HNF1α能明显减轻肝纤维化。

进一步研究表明,HNF1α能直接结合肝细胞SHP-1(SH2 domain-containing phosphatase-1)的启动子,由此调控SHP-1的转录表达。当SHP-1受到抑制的时候,HNF1α就无法在大鼠中起到抗纤维化的效果。

研究人员指出,在原代肝细胞中抑制HNF1α,会激活NF-κB和JAK/STAT通路,启动一个炎症性反馈回路。这一回路通过影响肝细胞和肝星状细胞之间的互作,促进肝细胞损伤的发展。

这项研究向人们展示,受损肝细胞在肝纤维化中起到了活跃的作用。在肝细胞中干预HNF1α调控的炎症性反馈回路,将有助于治疗慢性肝脏疾病。

推荐原文:An HNF1α-regulated feedback circuit modulates hepatic fibrogenesis via the crosstalk between hepatocytes and hepatic stellate cells

原文摘要:Hepatocytes are critical for the maintenance of liver homeostasis, but its involvement in hepatic fibrogenesis remains elusive. Hepatocyte nuclear factor 1α (HNF1α) is a liver-enriched transcription factor that plays a key role in hepatocyte function. Our previous study revealed a significant inhibitory effect of HNF1α on hepatocellular carcinoma. In this study, we report that the expression of HNF1α is significantly repressed in both human and rat fibrotic liver. Knockdown of HNF1α in the liver significantly aggravates hepatic fibrogenesis in either dimethylnitrosamine (DMN) or bile duct ligation (BDL) model in rats. In contrast, forced expression of HNF1α markedly alleviates hepatic fibrosis. HNF1α regulates the transcriptional expression of SH2 domain-containing phosphatase-1 (SHP-1) via directly binding to SHP-1 promoter in hepatocytes. Inhibition of SHP-1 expression abrogates the anti-fibrotic effect of HNF1α in DMN-treated rats. Moreover, HNF1α repression in primary hepatocytes leads to the activation of NF-κB and JAK/STAT pathways and initiates an inflammatory feedback circuit consisting of HNF1α, SHP-1, STAT3, p65, miR-21 and miR-146a, which sustains the deregulation of HNF1α in hepatocytes. More interestingly, a coordinated crosstalk between hepatocytes and hepatic stellate cells (HSCs) participates in this positive feedback circuit and facilitates the progression of hepatocellular damage. Our findings demonstrate that impaired hepatocytes play an active role in hepatic fibrogenesis. Early intervention of HNF1α-regulated inflammatory feedback loop in hepatocytes may have beneficial effects in the treatment of chronic liver diseases.

来源: Cell Research 浏览次数:1

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