An HNF1 alpha-regulated feedback circuit modulates hepatic fibrogenesis via the crosstalk between hepatocytes and hepatic stellate cells

作者：Qian, Hui; Deng, Xing; Huang, Zhao-Wei; Wei, Ji; Ding, Chen-Hong; Feng, Ren-Xin; Zeng, Xin; Chen, Yue-Xiang; Ding, Jin; Qiu, Lei; Hu, Zhen-Lin; Zhang, Xin; Wang, Hong-Yang; Zhang, Jun-Ping; Xie, Wei-Fen^*

来源：Cell Research, 2015, 25(8): 930-945.

DOI：10.1038/cr.2015.84

• Hepatocyte nuclear factor 1 alpha
• liver fibrosis
• SH2 domain-containing phosphatase-1
• microRNA
• feedback
• crosstalk

Hepatocytes are critical for the maintenance of liver homeostasis, but its involvement in hepatic fibrogenesis remains elusive. Hepatocyte nuclear factor 1 alpha (HNF1 alpha) is a liver-enriched transcription factor that plays a key role in hepatocyte function. Our previous study revealed a significant inhibitory effect of HNF1 alpha on hepatocellular carcinoma. In this study, we report that the expression of HNF1 alpha is significantly repressed in both human and rat fibrotic liver. Knockdown of HNF1 alpha in the liver significantly aggravates hepatic fibrogenesis in either dimethylnitrosamine (DMN) or bile duct ligation (BDL) model in rats. In contrast, forced expression of HNF1 alpha markedly alleviates hepatic fibrosis. HNF1 alpha 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 HNF1 alpha in DMN-treated rats. Moreover, HNF1 alpha repression in primary hepatocytes leads to the activation of NF-kappa B and JAK/STAT pathways and initiates an inflammatory feedback circuit consisting of HNF1 alpha, SHP-1, STAT3, p65, miR-21 and miR-146a, which sustains the deregulation of HNF1 alpha 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 HNF1 alpha-regulated inflammatory feedback loop in hepatocytes may have beneficial effects in the treatment of chronic liver diseases.

• 出版日期2015-8
• 单位天津市中医药研究院附属医院; 中国人民解放军第二军医大学