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GIV/Girdin is a central hub for profibrogenic signalling networks during liver fibrosis

Nature Communications volume 5, Article number: 4451 (2014) | Download Citation

Abstract

Progressive liver fibrosis is characterized by the deposition of collagen by activated hepatic stellate cells (HSCs). Activation of HSCs is a multiple receptor-driven process in which profibrotic signals are enhanced and antifibrotic pathways are suppressed. Here we report the discovery of a signalling platform comprising G protein subunit, Gαi and GIV, its guanine exchange factor (GEF), which serves as a central hub within the fibrogenic signalling network initiated by diverse classes of receptors. GIV is expressed in the liver after fibrogenic injury and is required for HSC activation. Once expressed, GIV enhances the profibrotic (PI3K-Akt-FoxO1 and TGFβ-SMAD) and inhibits the antifibrotic (cAMP-PKA-pCREB) pathways to skew the signalling network in favour of fibrosis, all via activation of Gαi. We also provide evidence that GIV may serve as a biomarker for progression of fibrosis after liver injury and a therapeutic target for arresting and/or reversing HSC activation during liver fibrosis.

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Acknowledgements

We thank Marilyn Farquhar (UCSD) and Mikel Garcia-Marcos (Boston U) for their helpful comments and critiques during the preparation of this manuscript, Katsumi Miyai (Pathology, UCSD) for generously giving us access to liver autopsy samples used in this work, Timo Meerloo for help with the preparation of semithin cryosections used to perform the immunofluorescence analysis and Robert Esteban (Ventana Inc.) for optimization of IHC staining of liver sections. This work was supported by NIH grants CA160911 and DK099226, CAMS (Burroughs Wellcome Fund) and CSDA (Doris Duke Charitable Foundation) Awards to P.G. I.L.-S. was supported by American Heart Association (AHA no. 14POST20050025); Y.M. was supported by the Sarah Rogers Fellowship (UCSD). D.A.B was supported by P42ES010337, S.B.H. by Veterans Affairs Research Service, E.S. by R01AA020172, R01DK085252 and P42ES010337, and F.M. by NIH HL091061.

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Affiliations

  1. Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA

    • Inmaculada Lopez-Sanchez
    • , Ying Dunkel
    • , Yoon-Seok Roh
    • , Yash Mittal
    • , Samuele De Minicis
    • , Nakon Aroonsakool
    • , Fiona Murray
    • , Ekihiro Seki
    • , David A. Brenner
    •  & Pradipta Ghosh
  2. Ventana Medical Systems Inc, 1910 East Innovation Park Drive, Tucson, Arizona 85755, USA

    • Andrea Muranyi
    • , Shalini Singh
    •  & Kandavel Shanmugam
  3. Veterans Affairs Medical Center, 3350 La Jolla Village Drive, San Diego, La Jolla, California 92161, USA

    • Samuel B. Ho

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Contributions

I.L.-S. and P.G. designed, performed and analysed most of the experiments in this work and also wrote the paper. Y.D. and Y.M. performed experiments and analysed data. Liver fractionation and chronic injury of mice were carried out by Y.-S.R. and S.D.M. and supervised by E.S. and D.A.B. A.M., S.S. and K.S. performed IHC at Ventana. N.A. and F.M. carried out radioimmunoassay assay for cAMP. S.B.H. contributed human liver samples used in this study. P.G. supervised and funded the project.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Pradipta Ghosh.

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https://doi.org/10.1038/ncomms5451

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