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An Elf2-like transcription factor acts as repressor of the mouse ecto-5′-nucleotidase gene expression in hepatic myofibroblasts

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Abstract

Hepatic fibrosis represents a pathological wound healing and tissue repair process triggered in response to chronic liver injury. A heterogeneous population of activated non-parenchymal liver cells, known as liver myofibroblasts, functions as the effector cells in hepatic fibrosis. Upon activation, liver myofibroblasts become fibrogenic, acquiring contractile properties and increasing collagen production capacity, while developing enhanced sensitivity to endogenous molecules and factors released in the local microenvironment. Hepatic extracellular adenosine is a bioactive small molecule, increasingly recognized as an important regulator of liver myofibroblast functions, and an important mediator in the pathogenesis of liver fibrosis overall. Remarkably, ecto-5′-nucleotidase/Nt5e/Cd73 enzyme, which accounts for the dominant adenosine-generating activity in the extracellular medium, is expressed by activated liver myofibroblasts. However, the molecular signals regulating Nt5e gene expression in liver myofibroblasts remain poorly understood. Here, we show that activated mouse liver myofibroblasts express Nt5e gene products and characterize the putative Nt5e minimal promoter in the mouse species. We describe the existence of an enhancer sequence upstream of the mouse Nt5e minimal promoter and establish that the mouse Nt5e minimal promoter transcriptional activity is negatively regulated by an Elf2-like Ets-related transcription factor in activated mouse liver myofibroblasts.

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Acknowledgements

Funding was provided by Gilead Sciences Research Scholars Program in Liver Disease Award UAMS# 271G141616-01 to MF, NIH – NIDDK R56DK076735 to JAD, and NIH – NCRR/NIH –NCATS #UL1TR000039 - University of Arkansas for Medical Sciences Institutional Support.

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR, 72205, USA

    Michel Fausther, Elise G. Lavoie, Jessica R. Goree & Jonathan A. Dranoff

  2. Research Service, Central Arkansas Veterans Administration Health System, Little Rock, AR, 72205, USA

    Michel Fausther, Elise G. Lavoie, Jessica R. Goree & Jonathan A. Dranoff

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  1. Michel Fausther
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  2. Elise G. Lavoie
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  4. Jonathan A. Dranoff
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Contributions

MF designed, performed, and analyzed the experiments shown in Figs. 1, 2, 3, 4, 5, 6, conceived the study, and wrote the paper. EGL designed, performed, and analyzed the experiments shown in Figs. 1 and 6. JRG performed and provided technical assistance for experiments shown in Figs. 1 and 6. JAD conceived the study and edited the paper. All authors reviewed the results and approved the final version of the manuscript.

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Correspondence to Michel Fausther.

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Michel Fausther declares that he has no conflict of interest.

Elise G. Lavoie declares that she has no conflict of interest.

Jessica R. Goree declares that she has no conflict of interest.

Jonathan A. Dranoff declares that he has no conflict of interest.

Ethical approval

All mouse experiments were performed in accordance with regulations approved by the University of Arkansas for Medical Sciences Institutional Animal Care and Use Committee.

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Fausther, M., Lavoie, E.G., Goree, J.R. et al. An Elf2-like transcription factor acts as repressor of the mouse ecto-5′-nucleotidase gene expression in hepatic myofibroblasts. Purinergic Signalling 13, 417–428 (2017). https://doi.org/10.1007/s11302-017-9570-7

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