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Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression in male mice

Author

Listed:
  • Hui Xia

    (McGill University
    McGill University)

  • Catherine R. Dufour

    (McGill University)

  • Younes Medkour

    (McGill University)

  • Charlotte Scholtes

    (McGill University)

  • Yonghong Chen

    (McGill University
    McGill University)

  • Christina Guluzian

    (McGill University
    McGill University)

  • Wafa B’chir

    (McGill University)

  • Vincent Giguère

    (McGill University
    McGill University)

Abstract

Nonalcoholic steatohepatitis (NASH) is epidemiologically associated with obesity and diabetes and can lead to liver cirrhosis and hepatocellular carcinoma if left untreated. The intricate signaling pathways that orchestrate hepatocyte energy metabolism and cellular stress, intrahepatic cell crosstalk, as well as interplay between peripheral tissues remain elusive and are crucial for the development of anti-NASH therapies. Herein, we reveal E3 ligase FBXW7 as a key factor regulating hepatic catabolism, stress responses, systemic energy homeostasis, and NASH pathogenesis with attenuated FBXW7 expression as a feature of advanced NASH. Multiomics and pharmacological intervention showed that FBXW7 loss-of-function in hepatocytes disrupts a metabolic transcriptional axis conjointly controlled by the nutrient-sensing nuclear receptors ERRα and PPARα, resulting in suppression of fatty acid oxidation, elevated ER stress, apoptosis, immune infiltration, fibrogenesis, and ultimately NASH progression in male mice. These results provide the foundation for developing alternative strategies co-targeting ERRα and PPARα for the treatment of NASH.

Suggested Citation

  • Hui Xia & Catherine R. Dufour & Younes Medkour & Charlotte Scholtes & Yonghong Chen & Christina Guluzian & Wafa B’chir & Vincent Giguère, 2023. "Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression in male mice," Nature Communications, Nature, vol. 14(1), pages 1-24, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42785-3
    DOI: 10.1038/s41467-023-42785-3
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    References listed on IDEAS

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    1. Jae Man Lee & Martin Wagner & Rui Xiao & Kang Ho Kim & Dan Feng & Mitchell A. Lazar & David D. Moore, 2014. "Nutrient-sensing nuclear receptors coordinate autophagy," Nature, Nature, vol. 516(7529), pages 112-115, December.
    2. Hui Xia & Charlotte Scholtes & Catherine R. Dufour & Carlo Ouellet & Majid Ghahremani & Vincent Giguère, 2022. "Insulin action and resistance are dependent on a GSK3β-FBXW7-ERRα transcriptional axis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
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