Volume 25, No 8, Aug 2015
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 25 Issue 8, August 2015: 930-945 | Open Access
ORIGINAL ARTICLES
An HNF1α-regulated feedback circuit modulates hepatic fibrogenesis via the crosstalk between hepatocytes and hepatic stellate cells
Hui Qian1,4,*, Xing Deng1,*, Zhao-Wei Huang1,4,*, Ji Wei1, Chen-Hong Ding1, Ren-Xin Feng1, Xin Zeng1, Yue-Xiang Chen1, Jin Ding3, Lei Qiu2, Zhen-Lin Hu2, Xin Zhang1, Hong-Yang Wang3, Jun-Ping Zhang2 and Wei-Fen Xie1
1Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
2Department of Biochemical Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
3The International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200433, China
4Current address: Department of Gastroenterology, 411th Hospital of PLA, Shanghai 200081, China
Correspondence: Wei-Fen Xie, Tel: +86-21-81885341; Fax: +86-21-8188-6924 E-mail: weifenxie@medmail.com.cn; Jun-Ping Zhang, Tel: +86-21-81871328(jpzhang08@hotmail.com)
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.
10.1038/cr.2015.84
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