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| 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
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| 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.
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| 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.
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| 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 |
| E-mail(s) |
guido.hooiveld@wur.nl
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| Organization name |
Wageningen University
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| Department |
Div. Human Nutrition & Health
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| Lab |
Nutrition, Metabolism & Genomics Group
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| Street address |
HELIX, Stippeneng 4
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| City |
Wageningen |
| ZIP/Postal code |
NL-6708WE |
| Country |
Netherlands |
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| Platforms (1) |
| GPL11533 |
[MoGene-1_1-st] Affymetrix Mouse Gene 1.1 ST Array [transcript (gene) version] |
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| Samples (24)
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| 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 |
| GSM4745259 |
G245_B05_04_KEAP1_1PH: Primary hepatocytes, KEAP1Δhepa mouse, replicate 1 |
| GSM4745260 |
G245_B07_05_KEAP1_2PH: Primary hepatocytes, KEAP1Δhepa mouse, replicate 2 |
| GSM4745261 |
G245_B09_06_KEAP1_3PH: Primary hepatocytes, KEAP1Δhepa mouse, replicate 3 |
| GSM4745262 |
G245_C05_07_NEMO_1PH_3: Primary hepatocytes, NEMOΔhepa mouse, replicate 1 |
| GSM4745263 |
G245_C07_08_NEMO_2PH: Primary hepatocytes, NEMOΔhepa mouse, replicate 2 |
| GSM4745264 |
G245_C09_09_NEMO_3PH: Primary hepatocytes, NEMOΔhepa mouse, replicate 3 |
| GSM4745265 |
G245_D05_10_2KO_1PH_2: Primary hepatocytes, NEMOΔhepa/KEAP1Δhepa mouse, replicate 1 |
| GSM4745266 |
G245_D07_11_2KO_2PH_2: Primary hepatocytes, NEMOΔhepa/KEAP1Δhepa mouse, replicate 2 |
| GSM4745267 |
G245_D09_12_2KO_3PH: Primary hepatocytes, NEMOΔhepa/KEAP1Δhepa mouse, replicate 3 |
| GSM4745268 |
G245_E05_13_WT_1L_2: Liver, NEMOf/f mouse, replicate 1 |
| GSM4745269 |
G245_E07_14_WT_2L: Liver, NEMOf/f mouse, replicate 2 |
| GSM4745270 |
G245_E09_15_WT_3L: Liver, NEMOf/f mouse, replicate 3 |
| GSM4745271 |
G245_F05_16_KEAP1_1L: Liver, KEAP1Δhepa mouse, replicate 1 |
| GSM4745272 |
G245_F07_17_KEAP1_2L: Liver, KEAP1Δhepa mouse, replicate 2 |
| GSM4745273 |
G245_F09_18_KEAP1_3L: Liver, KEAP1Δhepa mouse, replicate 3 |
| GSM4745274 |
G245_G05_19_NEMO_1L: Liver, NEMOΔhepa mouse, replicate 1 |
| GSM4745275 |
G245_G07_20_NEMO_2L: Liver, NEMOΔhepa mouse, replicate 2 |
| GSM4745276 |
G245_G09_21_NEMO_3L: Liver, NEMOΔhepa mouse, replicate 3 |
| GSM4745277 |
G245_H05_22_2KO_1L: Liver, NEMOΔhepa/KEAP1Δhepa mouse, replicate 1 |
| GSM4745278 |
G245_H07_23_2KO_2L: Liver, NEMOΔhepa/KEAP1Δhepa mouse, replicate 2 |
| GSM4745279 |
G245_H09_24_2KO_3L: Liver, NEMOΔhepa/KEAP1Δhepa mouse, replicate 3 |
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| Relations |
| BioProject |
PRJNA659240 |
| 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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