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Selective disruption of NRF2-KEAP1 interaction leads to NASH resolution and reduction of liver fibrosis in mice

ABSTRACT: The transcription factor NRF2 and its negative regulator KEAP1 are master regulators of redox, metabolic and protein homeostasis, detoxification and appear therefore as attractive drug targets for the treatment of NASH. S217879 a small molecule disrupting the KEAP1-NRF2 interaction has been highly characterized using various molecular and cellular assays. It was then evaluated in two different NASH-relevant preclinical models, and RNAseq data were obtained with samples from Diet-induced Obesity NASH (DIO NASH) mouse model. In DIO NASH mice, S217879 treatment resulted in a significant improvement of established liver injury with clear reduction in both NAS score as well as liver fibrosis. Alpha SMA and Col1A1 staining as well as quantification of liver hydroxyproline levels confirmed the reduction in liver fibrosis in response to S217879. RNA seq analyses revealed major alterations in the liver transcriptome in response to S217879 with activation of NRF2-dependent gene transcription as well as a marked inhibition of key signaling pathways driving disease progression

ORGANISM(S): Mus musculus

PROVIDER: GSE212644 | GEO | 2022/09/07

REPOSITORIES: GEO

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Project description: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∆hepa) mice were crossed with hepatocyte-specific KEAP1 knock-out (KEAP1∆hepa) 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∆hepa livers was rescued after deleting KEAP1. As a consequence, NEMO∆hepa/KEAP1∆hepa livers showed reduced apoptosis compared to NEMO∆hepa livers as well as a dramatic downregulation of genes involved in cell cycle regulation and DNA replication. Consequently, NEMO∆hepa/KEAP1∆hepa compared to NEMOΔhepa 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.

Project description:Background and aims: Oxidative stress triggers nonalcoholic steatohepatitis (NASH) and fibrosis. Previous animal studies demonstrated that the transcription factor NRF2, the master regulator of antioxidant response, protects against NASH and fibrosis. S217879, a new generation NRF2 activator has been recently shown to trigger NASH resolution and to reduce established fibrosis in rodents. Our aim was to evaluate the therapeutic potential of S217879 in human metabolic associated fatty liver disease (MAFLD) and its underlying mechanisms using the relevant experimental 3D model of patient-derived precision cut liver slices (PCLS). Methods: We treated PCLS from 12 patients with MAFLD with S217879 or Elafibranor (PPARα/δ agonist used as a referent molecule) for two days. Safety and efficacy profiles, steatosis, liver injury, inflammation and fibrosis were assessed as well as mechanisms involved in NASH pathophysiology, namely antioxidant response, autophagy and ER-stress. Results: Neither Elafibranor nor S217879 had toxic effects at the tested concentrations on human PCLS with MAFLD. PPARα/δ and NRF2 target genes (PDK4, FGF21 and NQO1, HMOX1, respectively) were strongly upregulated in PCLS in response to Elafibranor and S217879, respectively. Compared to untreated PCLS, Elafibranor and S217879-treated slices displayed lower triglycerides and reduced inflammation (IL-1β, IL-6, CCL2). Additional inflammatory markers (CCL5, STING, ICAM-1, VCAM-1) were downregulated by S217879. S217879 but not Elafibranor lowered DNA damages (p-H2A.X, RAD51, XRCC1) and apoptosis (cleaved Caspase-3), and inhibited fibrogenesis markers expression (α-SMA, COL1A1, COL1A2). Such effects were mediated through an improvement of lipid metabolism, activated antioxidant response and enhanced autophagic flux, without effect on ER-stress. Conclusion: This study highlights the therapeutic potential of a new NRF2 activator for NASH using patient-derived PCLS supporting the evaluation of NRF2 activating strategies in clinical trials.

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Selective disruption of NRF2-KEAP1 interaction leads to NASH resolution and reduction of liver fibrosis in mice

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