An HNF 1α-regulated feedback circuit modulates hepatic fibrogenesis via the crosstalk between hepatocytes and hepatic stellate cells  

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

机构地区：[1]Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China [2]Department of Biochemical Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai 200433, China [3]The International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200433, China [4]Department of Gastroenterology, 411th Hospital of PLA,Shanghai 200081, China

出　　处：《Cell Research》2015年第8期930-945,共16页细胞研究（英文版）

基　　金：Acknowledgment We thank Dr Zhao-Hui Wei （TigerMed Co., Ltd., Shanghai, China） for assistance on statistical analysis. This work was supported by the National Natural Science Foundation of China （81470871 ; Key Program, 81230011; Creative Research Groups, 30921006） and Shanghai Science and Technology Committee for the Key Projects （13JC1407400）.

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. HN- Fla 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-I, STAT3, p65, miR-21 and miR-146a, which sustains the deregulation of HNF1α in hepatocytes. More interestingly, a coordinated crosstalk between hepatocytes and hepatic steUate 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.

关 键 词：Hepatocyte nuclear factor 1α liver fibrosis SH2 domain-containing phosphatase-1 microRNA feedback CROSSTALK 

分 类 号：Q78[生物学—分子生物学] Q55