Hepatocyte-specific NRF2 activation controls fibrogenesis and carcinogenesis in steatohepatitis

Abstract:

Background & Aims Inflammation in chronic liver diseases induces oxidative stress and thus may contribute to progression of liver injury, fibrosis, and carcinogenesis. The KEAP1/NRF2 axis is a major regulator of cellular redox balance. In the present study, we investigated whether the KEAP1/NRF2 system is involved in liver disease progression in human and mice.

Methods The clinical relevance of oxidative stress was investigated in a well-characterized cohort of NAFLD patients (n=63) by liver RNA sequencing and correlated with histological and clinical parameters. For functional analysis hepatocyte-specific NEMO knock-out (NEMO Δhepa) mice were crossed with hepatocyte-specific KEAP1 knock-out (KEAP1 Δhepa) mice.

Results Immunohistochemical analysis of human liver sections showed increased oxidative stress and high NRF2 expression in patients with chronic liver disease. RNA sequencing of liver samples in a human pediatric NAFLD cohort revealed a significant increase of NRF2 activation correlating with the grade of inflammation, but not with the grade of steatosis, which could be confirmed in a second adult NASH cohort. In mice, microarray analysis revealed that KEAP1 deletion induces NRF2 target genes involved in glutathione metabolism and xenobiotic stress (e.g., Nqo1). Furthermore, deficiency of one of the most important antioxidants, glutathione (GSH), in NEMO Δhepa livers was rescued after deleting KEAP1. As a consequence, NEMO Δhepa/KEAP1 Δhepa livers showed reduced apoptosis compared to NEMO Δhepa livers as well as a dramatic downregulation of genes involved in cell cycle regulation and DNA replication. Consequently, NEMO Δhepa/KEAP1 Δhepa compared to NEMO Δhepa livers displayed decreased fibrogenesis, lower tumor incidence, reduced tumor number, and decreased tumor size.

Conclusions NRF2 activation in NASH patients correlates with the grade of inflammation, but not steatosis. Functional analysis in mice demonstrated that NRF2 activation in chronic liver disease is protective by ameliorating fibrogenesis, initiation and progression of hepatocellular carcinogenesis.

SEEK ID: https://seek.lisym.org/publications/283

DOI: 10.1016/j.jhep.2020.09.037

Projects: LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

Publication type: Journal

Journal: Journal of Hepatology

Citation: Journal of Hepatology,S0168827820336953

Date Published: 1st Oct 2020

Registered Mode: by DOI

Authors: Antje Mohs, Tobias Otto, Kai Markus Schneider, Mona Peltzer, Mark Boekschoten, Christian H. Holland, Christian A. Hudert, Laura Kalveram, Susanna Wiegand, Julio Saez-Rodriguez, Thomas Longerich, Jan G. Hengstler, Christian Trautwein

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Mohs, A., Otto, T., Schneider, K. M., Peltzer, M., Boekschoten, M., Holland, C. H., Hudert, C. A., Kalveram, L., Wiegand, S., Saez-Rodriguez, J., Longerich, T., Hengstler, J. G., & Trautwein, C. (2021). Hepatocyte-specific NRF2 activation controls fibrogenesis and carcinogenesis in steatohepatitis. In Journal of Hepatology (Vol. 74, Issue 3, pp. 638–648). Elsevier BV. https://doi.org/10.1016/j.jhep.2020.09.037
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Created: 27th Oct 2020 at 10:09

Last updated: 27th Oct 2020 at 10:10

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