title: An HNF1α-regulated feedback circuit modulates hepatic fibrogenesis via the crosstalk between hepatocytes and hepatic stellate cells.
abstract: 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.
authors.affiliation: 1] Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China [2] Current address: Department of Gastroenterology, 411th Hospital of PLA, Shanghai 200081, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Qian
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Deng
authors.affiliation: 1] Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China [2] Current address: Department of Gastroenterology, 411th Hospital of PLA, Shanghai 200081, China.
authors.forename: Zhao-Wei
authors.initials: ZW
authors.lastname: Huang
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Chen-Hong
authors.initials: CH
authors.lastname: Ding
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Ren-Xin
authors.initials: RX
authors.lastname: Feng
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Yue-Xiang
authors.initials: YX
authors.lastname: Chen
authors.affiliation: The International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200433, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Ding
authors.affiliation: Department of Biochemical Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Department of Biochemical Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Zhen-Lin
authors.initials: ZL
authors.lastname: Hu
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: The International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200433, China.
authors.forename: Hong-Yang
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Department of Biochemical Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
authors.forename: Jun-Ping
authors.initials: JP
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Wei-Fen
authors.initials: WF
authors.lastname: Xie
mesh_terms: D000818:Animals; D002450:Cell Communication; D025461:Feedback, Physiological; D005355:Fibrosis; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000096:biosynthesis*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D050791:STAT Transcription Factors / Q000378:metabolism
chemical_list: D051538:Hepatocyte Nuclear Factor 1-alpha; D016328:NF-kappa B; D050791:STAT Transcription Factors; D053612:Janus Kinases