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Series GSE156838 Query DataSets for GSE156838
Status Public on May 26, 2021
Title NRF2/KEAP1 in hepatocytes controls fibro- and carcinogenesis in chronic liver disease
Organism Mus musculus
Experiment type Expression profiling by array
Summary 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.
Overall design Microarray analysis was performed on livers or primary hepatocytes of control, hepatocyte-specific NEMO knockout mice, hepatocyte-specific KEAP1 knockout mice, or hepatocyte-specific NEMO/KEAP1 double knockout mice.
Contributor(s) Mohs A, Otto T, Boekschoten MV, Trautwein C
Citation(s) 33342543
Submission date Aug 25, 2020
Last update date May 30, 2021
Contact name Guido Hooiveld
Organization name Wageningen University
Department Div. Human Nutrition & Health
Lab Nutrition, Metabolism & Genomics Group
Street address HELIX, Stippeneng 4
City Wageningen
ZIP/Postal code NL-6708WE
Country Netherlands
Platforms (1)
GPL11533 [MoGene-1_1-st] Affymetrix Mouse Gene 1.1 ST Array [transcript (gene) version]
Samples (24)
GSM4745256 G245_A05_01_WT_1PH: Primary hepatocytes, NEMOf/f mouse, replicate 1
GSM4745257 G245_A07_02_WT_2PH: Primary hepatocytes, NEMOf/f mouse, replicate 2
GSM4745258 G245_A09_03_WT_3PH: Primary hepatocytes, NEMOf/f mouse, replicate 3
BioProject PRJNA659240

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Supplementary file Size Download File type/resource
GSE156838_RAW.tar 102.1 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table

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