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Mol Ther Nucleic Acids. 2019 Dec 6;18:1009-1022. doi: 10.1016/j.omtn.2019.10.025. Epub 2019 Oct 31.

NPAS2 Contributes to Liver Fibrosis by Direct Transcriptional Activation of Hes1 in Hepatic Stellate Cells.

Author information

1
Department of Pain Treatment, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
2
State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
3
Department of General Surgery, The 75th Group Army Hospital, Dali, Yunnan 671000, China.
4
Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
5
College and Hospital of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China.
6
Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Hematology, Xi'an Central Hospital, Xi'an, Shaanxi 710003, China. Electronic address: fzzxmj@126.com.
7
Department of Pain Treatment, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, China. Electronic address: yanzytdtt@163.com.
8
Department of Hepatobiliary Surgery, Shaanxi Provincial People's Hospital, Xi'an 710068, China. Electronic address: changhulin_spph@163.com.

Abstract

Recently, emerging evidence shows that dysregulation of circadian genes is closely associated with liver fibrosis. However, how dysregulation of circadian genes promotes liver fibrosis is unknown. In this study, we show that neuronal PAS domain protein 2 (NPAS2), one of the core circadian molecules that has been shown to promote hepatocarcinoma cell proliferation, significantly contributed to liver fibrogenesis. NPAS2 is upregulated in hepatic stellate cells (HSCs) after fibrogenic injury, which subsequently contributes to the activation of HSCs. Mechanistically, NPAS2 plays a profibrotic role via direct transcriptional activation of hairy and enhancer of split 1 (Hes1), a critical transcriptor of Notch signaling for the fibrogenesis process, in HSCs. Our findings demonstrate that NPAS2 plays a critical role in liver fibrosis through direct transcriptional activation of Hes1, indicating that NPAS2 may serve as an important therapeutic target to reverse the progression of liver fibrosis.

KEYWORDS:

Hes1; circadian gene; hepatic stellate cell; liver fibrosis; neuronal PAS domain protein 2

PMID:
31778954
DOI:
10.1016/j.omtn.2019.10.025
Free PMC Article

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