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NRF2 activates growth factor genes and downstream AKT signaling to induce mouse and human hepatomegaly

  • Author Footnotes
    $ These authors contributed equally
    Feng He
    Footnotes
    $ These authors contributed equally
    Affiliations
    Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
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  • Author Footnotes
    $ These authors contributed equally
    Laura Antonucci
    Footnotes
    $ These authors contributed equally
    Affiliations
    Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
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  • Author Footnotes
    $ These authors contributed equally
    Shinichiro Yamachika
    Footnotes
    $ These authors contributed equally
    Affiliations
    Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
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  • Zechuan Zhang
    Affiliations
    Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu Province, China
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  • Koji Taniguchi
    Affiliations
    Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
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  • Atsushi Umemura
    Affiliations
    Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
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  • Georgia Hatzivassiliou
    Affiliations
    Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
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  • Merone Roose-Girma
    Affiliations
    Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
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  • Miguel Reina-Campos
    Affiliations
    Cancer Metabolism and Signaling Networks Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
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  • Angeles Duran
    Affiliations
    Cancer Metabolism and Signaling Networks Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
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  • Maria T. Diaz-Meco
    Affiliations
    Cancer Metabolism and Signaling Networks Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
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  • Jorge Moscat
    Affiliations
    Cancer Metabolism and Signaling Networks Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
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  • Beicheng Sun
    Correspondence
    Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu Province, China. Tel.: +86 25 83105892; fax: +86 25 86560946
    Affiliations
    Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu Province, China
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  • Michael Karin
    Correspondence
    Corresponding authors. Addresses: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Tel.: +1 858 534 1361; fax: +1 858 534 0848
    Affiliations
    Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA

    Department of Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
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  • Author Footnotes
    $ These authors contributed equally
Published:February 24, 2020DOI:https://doi.org/10.1016/j.jhep.2020.01.023

      Highlights

      • Liver p62 accumulation and constitutive NRF2 activation lead to liver lipid buildup, glycogen synthesis and hepatomegaly.
      • NRF2 activation mediates transcriptional induction of PDGF and EGF receptor ligands that activate AKT.
      • AKT and tyrosine kinase inhibitors block NRF2-mediated AKT activation and hepatomegaly.
      • NRF2-AKT signaling is elevated in HSOS- and AIH-related human hepatomegaly.

      Background & Aims

      Hepatomegaly can be triggered by insulin and insulin-unrelated etiologies. Insulin acts via AKT, but how other challenges cause hepatomegaly is unknown.

      Methods

      Since many hepatomegaly-inducing toxicants and stressors activate NRF2, we examined the effect of NRF2 activation on liver size and metabolism using a conditional allele encoding a constitutively active NRF2 variant to generate Nrf2Act-hep mice in which NRF2 is selectively activated in hepatocytes. We also used adenoviruses encoding variants of the autophagy adaptor p62/SQSTM1, which activates liver NRF2, as well as liver-specific ATG7-deficient mice (Atg7Δhep) and liver specimens from patients with hepatic sinusoidal obstruction syndrome (HSOS) and autoimmune hepatitis (AIH). RNA sequencing and cell signaling analyses were used to determine cellular consequences of NRF2 activation and diverse histological analyses were used to study effects of the different manipulations on liver and systemic pathophysiology.

      Results

      Hepatocyte-specific NRF2 activation, due to p62 accumulation or inhibition of KEAP1 binding, led to hepatomegaly associated with enhanced glycogenosis, steatosis and G2/M cell cycle arrest, fostering hyperplasia without cell division. Surprisingly, all manipulations that led to NRF2 activation also activated AKT, whose inhibition blocked NRF2-induced hepatomegaly and glycogenosis, but not NRF2-dependent antioxidant gene induction. AKT activation was linked to NRF2-mediated transcriptional induction of PDGF and EGF receptor ligands that signaled through their cognate receptors in an autocrine manner. Insulin and insulin-like growth factors were not involved. The NRF2-AKT signaling axis was also activated in human HSOS- and AIH-related hepatomegaly.

      Conclusions

      NRF2, a transcription factor readily activated by xenobiotics, oxidative stress and autophagy disruptors, may be a common mediator of hepatomegaly; its effects on hepatic metabolism can be reversed by AKT/tyrosine kinase inhibitors.

      Lay summary

      Hepatomegaly can be triggered by numerous etiological factors, including infections, liver cancer, metabolic disturbances, toxicant exposure, as well as alcohol abuse or drug-induced hepatitis. This study identified the oxidative stress response transcription factor NRF2 as a common mediator of hepatomegaly. NRF2 activation results in elevated expression of several growth factors. These growth factors are made by hepatocytes and activate their receptors in an autocrine fashion to stimulate the accumulation of glycogen and lipids that lead to hepatocyte and liver enlargement. The protein kinase AKT plays a key role in this process and its inhibition leads to reversal of hepatomegaly.

      Graphical abstract

      Keywords

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