An Nrf2-NF-kB cross-talk controls hepatocyte proliferation in the normal and injured liver
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ABSTRACT:
PROVIDER: PRJNA1140612 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30008176.fastq.gz | Fastqsanger.gz | |||
| SRR30008177.fastq.gz | Fastqsanger.gz | |||
| SRR30008178.fastq.gz | Fastqsanger.gz | |||
| SRR30008179.fastq.gz | Fastqsanger.gz | |||
| SRR30008180.fastq.gz | Fastqsanger.gz |
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Project description:The liver has remarkable regenerative and detoxification capacities, which require the Nrf2 and NF-kB transcription factors. Although their individual functions in hepatocytes are well characterized, knowledge about their cross-talk in the adult liver is limited. Therefore, we deleted the genes for Nrf2, the NF-kB subunit p65 or both genes in adult hepatocytes of mice using AAV8-Cre viruses. Loss of p65 or both genes caused spontaneous liver inflammation and necrosis, combined with a progressive increase in hepatocyte proliferation. Gene expression profiling identified individual and common target genes of both transcription factors, including genes involved in the control of cell proliferation.
2025-02-25 | GSE273213 | GEO
Project description:Human hepatocyte metaplasia in injured humanized mouse livers
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Project description:High density lipoproteins (HDL) promote homeostasis and counteract stressful tissue damage that underlie cardiovascular and other diseases by mediating reverse cholesterol transport, reducing inflammation, and abrogating oxidative damage. However, metabolically stressful conditions associated with atherosclerosis can impair these effects. Hepatocytes play a major role in the genesis and maturation of circulating HDL. Liver stress elicits marked regulatory changes to circulating HDL abundance and composition, which affect its functionality. Mechanisms linking liver stress to HDL functionality are incompletely understood. In this study, we sought to determine whether stress defending transcription factors nuclear factor erythroid 2 related factor-1 (NRF1) and -2 (NRF2) promote hepatocyte production of functional HDL. Using genetically engineered mouse models briefly fed a mild metabolically stressful diet, we investigated the effect of hepatocyte-specific deletion of NRF1, NRF2, or both on circulating HDL cholesterol level, protein composition, and function. Combined deletion, but not single gene deletion, reduced HDL cholesterol content as well as the capacity of HDL to accept cholesterol efflux from cultured macrophages and to counteract tumor necrosis factor a-induced inflammatory effect on cultured endothelial cells. This coincided with substantial alteration to the circulating HDL proteome, which correlated with liver gene expression profiles of corresponding proteins. Altogether, our findings show complementary actions by hepatocyte NRF1 and NRF2 play a role in shaping HDL composition and promote production of functionally viable HDL. Consequently, our study illuminates the possibility that enhancing stress defense programming in the liver may improve atheroprotective and perhaps other health promoting actions of HDL.
2023-07-03 | PXD042103 | Pride
Project description:Chemical induction of hepatocyte revitalization in injured human hepatocytes [RNA-seq 3]
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Project description:WGS and RNA-seq data for Nrf2 study
| EGAS00001001740 | EGA
Project description:Metabolic-associated steatohepatitis is a progressive fatty liver disease caused, in part, by hepatocyte stress linked to cholesterol overload. Counteracting this stress may be beneficial but there is insufficient understanding of underlying stress defenses to develop a therapeutic strategy. Here, we aimed to elucidate how stress-adaptive transcription factors, nuclear factor erythroid 2 related factor-1 (NRF1) and -2 (NRF2), counteract hepatic cholesterol overload and determine whether they function cooperatively. C57bl/6 mice were fed high fat, fructose, and cholesterol diet (HFFC). Expression profiling and phenotypic analyses were done on liver of mice with adult-onset and hepatocyte-specific deficiency of NRF1, NRF2, or both, and results compared to control. Chromatin immunoprecipitation (ChIP) sequencing was done and combined with expression profiles to identify genes that NRF1 and NRF2 interact with and regulate in vivo. Three weeks HFFC diet feeding to mice with NRF1 and NRF2 deficiency caused severe steatohepatitis and increased hepatic cholesterol storage. These outcomes did not occur in single gene-deficient mice or control. Expression profiling at a time preceding hepatic cholesterol overload and ChIP sequencing profiling revealed complementary gene regulation by NRF1 and NRF2 to promote cholesterol excretion and mitigate hazardous metabolic biproducts generated from converting cholesterol to bile acid. Consequently, combined gene deficiency, and not single-gene deficiency, increased liver oxidized protein level, decreased cholesterol in bile, and increased unconjugated bile acid in liver and bile. We discover, for the first time, that NRF1 and NRF2 work together to protect liver against damaging effects of excess cholesterol. Targeting these combined actions may prove an effective therapeutic strategy
2023-03-22 | PXD032069 | Pride
Project description:The transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates an array of cytoprotective genes, yet studies in transgenic mice have led to conflicting reports on its role in liver regeneration. We aimed to test the hypothesis that pharmacological activation of Nrf2 would enhance liver regeneration. Wild type (WT) and Nrf2 null mice were administered bardoxolone methyl (CDDO-Me), a potent activator of Nrf2 that has entered clinical development, and then subjected to partial hepatectomy (PHx). CDDO-Me enhanced the rate of restoration of liver volume and improved liver function (multispectral optoacoustic imaging in wild type, but not Nrf2 null, mice following two-thirds partial hepatectomy. These effects were associated with an increase in hepatocyte hypertrophy and proliferation, the suppression of immune and inflammatory signals, and metabolic remodeling in the remnant liver tissue.
2021-04-22 | GSE169242 | GEO
Project description:Background:
HCC incidence is increasing worldwide due to the obesity epidemic, which drives metabolic dysfunction-associated steatohepatitis (MASH) that can lead to HCC. However, the molecular pathways driving MASH-HCC are poorly understood. We have previously reported that male mice with haploinsufficiency of hypoxia-associated factor, HAF (SART1+/-) spontaneously develop MASH-HCC. However, the cell type(s) responsible for HCC associated with HAF loss are unclear.
Results:
We generated SART1-floxed mice, which were crossed with mice expressing Cre-recombinase within hepatocytes (Alb-Cre; hepS-/-) or myeloid cells (LysM-Cre, macS-/-). HepS-/- mice (both male and female) developed HCC associated with profound inflammatory and lipid dysregulation suggesting that HAF protects against HCC primarily within hepatocytes. HAF-deficient hepatocytes showed decreased P-p65 and P-p50 and in many components of the NF-kB pathway, which was recapitulated using HAF siRNA in vitro. HAF depletion also triggered apoptosis, suggesting that HAF protects against HCC by suppressing hepatocyte apoptosis. We show that HAF regulates NF-kB activity by regulating transcription of TRADD and RIPK1. Mice fed a high-fat diet (HFD) showed marked suppression of HAF, P-p65 and TRADD within their livers after 26 weeks, but showed profound upregulation of these proteins after 40 weeks, implicating deregulation of the HAF-NF-kB axis in the progression to MASH. In humans, HAF was significantly decreased in livers with simple steatosis but significantly increased in HCC compared with normal liver.
Conclusions:
HAF is novel transcriptional regulator of the NF-kB pathway and is a key determinant of cell fate during progression to MASH and MASH-HCC.
| MSV000095959 | MassIVE
Project description:Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that induces a battery of cytoprotective genes in response to oxidative/electrophilic stress. Kelch-like ECH associating protein 1 (Keap1) sequesters Nrf2 in the cytosol. The purpose of this study was to investigate the role of Nrf2 in regulating the mRNA of genes encoding drug metabolizing enzymes and xenobiotic transporters. Microarray analysis was performed in livers of Nrf2-null, wild-type, Keap1-knockdown mice with increased Nrf2 activation, and Keap1-hepatocyte knockout mice with maximum Nrf2 activation. In general, Nrf2 did not have a marked effect on uptake transporters, but the mRNAs of organic anion transporting polypeptide 1a1, sodium taurocholate cotransporting polypeptide, and organic anion transporter 2 were decreased with Nrf2 activation. The effect of Nrf2 on cytochrome P450 (Cyp) genes was minimal, with only Cyp2a5, Cyp2c50, Cyp2c54, and Cyp2g1 increased, and Cyp2u1 decreased with enhanced Nrf2 activation. However, Nrf2 increased mRNA of many other phase-I enzymes, such as aldo-keto reductases, carbonyl reductases, and aldehyde dehydrogenase 1. Many genes involved in phase-II drug metabolism were induced by Nrf2, including glutathione S -transferases, UDP- glucuronosyltransferases, and UDP-glucuronic acid synthesis enzymes. Efflux transporters, such as multidrug resistance-associated proteins, breast cancer resistant protein, as well as ATP-binding cassette g5 and g8 were induced by Nrf2. In conclusion, Nrf2 markedly alters hepatic mRNA of a large number of drug metabolizing enzymes and xenobiotic transporters, and thus Nrf2 plays a central role in xenobiotic metabolism and detoxification. We used microarrays to detail the global programme of gene expression in response to Nrf2 activation and identified distinct classes of up- and down-regulated genes. process. Gene expression in livers of Nrf2-null, WT, Keap1-KD, and Keap1-HKO mice was determined using Affymetrix Mouse 430.20 arrays by the KUMC Microarray Core Facility. Biological cRNA replicates (n=3) of each genotype were hybridized to an individual array.
2014-02-18 | E-GEOD-55001 | biostudies-arrayexpress