Chronic stress disrupts hepatic kynurenine pathway to subvert hepatic CD8+ T cell immunity and promote liver cancer
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE305657 | GEO | 2025/11/04
REPOSITORIES: GEO
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Project description:rs08-02_nad. Dark and light. Establish which transcripts are affected by changes in NAD concentration, and whether this depends on light/dark. Three genotypes: Two lines of Arabidopsis transformed to overexpress QPRT, an enzyme involved in NAD synthesis (NadC4.11 and NadC15.3) and a third control line transformed with an empty vector (162). Leaf discs from the two lines of the QPRT+ plants were incubated with quinolinate, the QPRT substrate, to boost leaf NAD. Discs from the empty vector control were incubated on a buffer withour quinolinate. The experiment was performed in the light and the dark. The aim is to compare the QPRT+ quinolinate samples with the empty vector samples, both for the sample series generated in the light and that generated in the dark. Keywords: treated vs untreated comparison
2009-11-01 | GSE15599 | GEO
Project description:Nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), an NAD+ synthetase in Preiss-Handler and salvage pathways, governs nuclear NAD+ homeostasis. This study investigated the role of NMNAT1 on alcohol-associated liver disease (ALD). Decreased NMNAT1 expression and activity were observed in the liver of alcohol-associated hepatitis patients and either liver or primary hepatocytes from ALD mice. F-box and WD repeat domain containing 7 (FBXW7)-regulated interferon regulatory factor 1 (IRF1) ubiquitination degradation contributed to alcohol-inhibited NMNAT1 transcriptional level. Hepatic NMNAT1 knockout aggravated alcohol-induced hepatic NAD+ decline and further hepatic steatosis and liver injury. Metabolomics and transcriptomics interaction revealed that cysteine sulfinic acid decarboxylase (CSAD)-regulated taurine pathway was involved in NMNAT1-disrupted hepatic lipid metabolism in ALD. Hepatic CSAD overexpression or taurine supply attenuated hepatic NMNAT1 knockout-aggravated ALD, respectively. Hepatic NMNAT1 loss inhibited NMN-protected ALD. Replenishing hepatic NMNAT1 reversed liver lipid accumulation in ALD mice. These findings identified NMNAT1 as a promising therapeutic target for ALD.
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Project description:KA-PARP1 was expressed in HeLa-KO PARP1 cells. Protein targets of KA-PARP1 were determined in cell lysate by using a DTB-modified NAD+analog.
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Project description:RNA sequencing was performed to elucidate the role of beta2-adrenergic receptor (Adrb2) signaling on CD8+ T cell function and memory development after a viral infection. This was done by transferring 2,000 Clone4-transgenic CD8+ T cells from Adrb2+/+ and Adrb2-/- mice were (co-transferred at a 1:1 mix) into naïve Balb/cJ mice and the mice were then infected with 10^6 PFU of vesicular stomatitis virus expressing hemaglutinin peptide from Influenza A PR/8 (VSV-HA). Cells were then FACS-purified on days 4, 5, 7, and 12 post-infection for RNA isolation. RNA from purified naïve CD8+ T cells from each genotype, before transfer, was used for day 0 samples.
2019-08-01 | GSE102478 | GEO
Project description:Supplemental NAD+ precursors show metabolic and functional benefits in rodent models of disease and are being explored as potential therapeutics in human studies. However, the wide range of processes that involve NAD+ in every cell and subcellular compartment make it difficult to narrow down mechanisms of action. Here we provide evidence that for a well-established benefit of NAD+ precursors in mice, faster liver regeneration, nearly the entire effect can be attributed to the concentration of NAD+ in hepatocyte mitochondria. We find that mitochondrial NAD+ concentration in hepatocytes of male mice is determined by the expression of the transporter SLC25A51 (MCART1), as has previously been shown in cultured cells. Heterozygous loss of SLC25A51 modestly decreases mitochondrial NAD+ content in multiple tissues and impairs liver regeneration, while hepatocyte-specific overexpression is sufficient to enhance regeneration comparably to the effect of systemic supplements, despite increasing NAD+ only in mitochondria. Thus, the hepatocyte mitochondrial NAD+ pool is a key determinant of the rate of liver regeneration.
2025-11-06 | PXD067549 | Pride
Project description:Supplemental NAD+ precursors show metabolic and functional benefits in rodent models of disease and are being explored as potential therapeutics in human studies. However, the wide range of processes that involve NAD+ in every cell and subcellular compartment make it difficult to narrow down mechanisms of action. Here we provide evidence that for a well-established benefit of NAD+ precursors in mice, faster liver regeneration, nearly the entire effect can be attributed to the concentration of NAD+ in hepatocyte mitochondria. We find that mitochondrial NAD+ concentration in hepatocytes of male mice is determined by the expression of the transporter SLC25A51 (MCART1), as has previously been shown in cultured cells. Heterozygous loss of SLC25A51 modestly decreases mitochondrial NAD+ content in multiple tissues and impairs liver regeneration, while hepatocyte-specific overexpression is sufficient to enhance regeneration comparably to the effect of systemic supplements, despite increasing NAD+ only in mitochondria. Thus, the hepatocyte mitochondrial NAD+ pool is a key determinant of the rate of liver regeneration.
2025-08-15 | MSV000098839 | MassIVE
Project description:Background & Aims: Liver ischemia-reperfusion (IR) injury is a common and serious complication in liver transplantation surgery. Disturbances of mitochondrial function, altered lipid metabolism, and insulin resistance are pathways shown to participate in acute and chronic liver diseases. NcoR1 was previously shown to integrate in all these damage pathways in liver, adipose tissue, and muscle, whereby its mechanistic role is not fully understood. Here, we delineated hepatocytic NcoR1 in liver ischemia-reperfusion injury. Methods: We established an IR model in mice, measured liver function related enzymes in serum, SOD, and combined these data with HE staining and PCR assays from liver sections and lysates, respectively to determine the extent of liver injury. We used mice with albumin-Cre/LoxP system mediated hepatocyte-specific NcoR1 depletion (NcoR1△Hep) to investigate the role of NcoR1 in the etiopathogenesis of liver IR and to delineate potential related mechanisms. We also analysed the impact of NcoR1 on oxidative stress mediated cell damage, including activation of NFB signaling activation in hepatocytes in gain and loss of function studies, using immunoblotting and immunofluorescence. Results: Upon ischemia and reperfusion injury (IR), as evidenced by increased levels of liver enzymes (ALT, AST), and inflammatory cytokines (Tnf, Mcp1 et al), NcoR1 expression levels decreased at both, mRNA and protein levels in total liver lysates. To discriminate cell type specific effects, we successfully established NcoR1△Hep mice, and found that depletion of Ncor1 in hepacotytes exhibited more severe liver injury from IR, as compared to NcoR1fl/fl control mice, as evidenced by the aforementioned parameters. Silencing NcoR1 or Ncor1 deficiency promoted both, parameters of inflammatory and oxidative stress such as Gclc, Gclm, Hmox1, and Ccl2, et, al. in AML12 cells and primary mouse hepatocytes, while NcoR1 over-expression shows the opposite results. Further, IR treated NcoR1△Hep mice displayed increased phosphorylation of p65, an essential parameter of the NFB signaling pathway, a critical mediator of stress signals in hepatocytes. Gene silencing of p65 in primary hepatocytes increased NcoR1 expression, suggesting that NFkB/p65 signaling is a negative regulator of NcoR1 expression. Conclusion: Our results indicate that damage mediated activation of NFB/p65 signaling decreases NcoR1 expression in hepatocytes, which is required for IR aggravation.
2025-05-10 | GSE296316 | GEO
Project description:Recent findings reveal the importance of tryptophan-initiated de novo nicotinamide adenine dinucleotide (NAD+) synthesis in the liver, a process previously considered secondary to biosynthesis from nicotinamide. Here we show that inhibiting α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) promotes de novo NAD+ synthesis and reduces DNA damage ex vivo, in vivo and in human liver organoid (HLO) models. In mouse models of MASLD/MASH, de novo NAD+ biosynthesis is suppressed, and transcriptomic DNA damage signatures correlate with disease severity; In humans, Mendelian randomization-based genetic analysis suggests a notable impact of genomic stress on liver disease susceptibility. Therapeutic inhibiting ACMSD in mice elevates liver NAD+ and reverses MASLD/MASH, mitigating fibrosis, inflammation and DNA damage. Similar outcomes are recapitulated in HLO models of steatohepatitis and DNA damage. Our findings highlight the benefits of ACMSD inhibition for boosting hepatic NAD+ and genomic protection, indicating its therapeutic promise in liver diseases marked by NAD+ and genomic stress.
2024-09-22 | GSE253217 | GEO
Project description:Recent findings reveal the importance of tryptophan-initiated de novo nicotinamide adenine dinucleotide (NAD+) synthesis in the liver, a process previously considered secondary to biosynthesis from nicotinamide. Here we show that inhibiting α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) promotes de novo NAD+ synthesis and reduces DNA damage ex vivo, in vivo and in human liver organoid (HLO) models. In mouse models of MASLD/MASH, de novo NAD+ biosynthesis is suppressed, and transcriptomic DNA damage signatures correlate with disease severity; In humans, Mendelian randomization-based genetic analysis suggests a notable impact of genomic stress on liver disease susceptibility. Therapeutic inhibiting ACMSD in mice elevates liver NAD+ and reverses MASLD/MASH, mitigating fibrosis, inflammation and DNA damage. Similar outcomes are recapitulated in HLO models of steatohepatitis and DNA damage. Our findings highlight the benefits of ACMSD inhibition for boosting hepatic NAD+ and genomic protection, indicating its therapeutic promise in liver diseases marked by NAD+ and genomic stress.
2024-09-23 | GSE253380 | GEO
Project description:Background & Aims: Liver ischemia-reperfusion (IR) injury is a common and serious complication in liver transplantation surgery. Disturbances of mitochondrial function, altered lipid metabolism, and insulin resistance are pathways shown to participate in acute and chronic liver diseases. NcoR1 was previously shown to integrate in all these damage pathways in liver, adipose tissue, and muscle, whereby its mechanistic role is not fully understood. Here, we delineated hepatocytic NcoR1 in liver ischemia-reperfusion injury. Methods: We established an IR model in mice, measured liver function related enzymes in serum, SOD, and combined these data with HE staining and PCR assays from liver sections and lysates, respectively to determine the extent of liver injury. We used mice with albumin-Cre/LoxP system mediated hepatocyte-specific NcoR1 depletion (NcoR1△Hep) to investigate the role of NcoR1 in the etiopathogenesis of liver IR and to delineate potential related mechanisms. We also analysed the impact of NcoR1 on oxidative stress mediated cell damage, including activation of NFB signaling activation in hepatocytes in gain and loss of function studies, using immunoblotting and immunofluorescence. Results: Upon ischemia and reperfusion injury (IR), as evidenced by increased levels of liver enzymes (ALT, AST), and inflammatory cytokines (Tnf, Mcp1 et al), NcoR1 expression levels decreased at both, mRNA and protein levels in total liver lysates. To discriminate cell type specific effects, we successfully established NcoR1△Hep mice, and found that depletion of Ncor1 in hepacotytes exhibited more severe liver injury from IR, as compared to NcoR1fl/fl control mice, as evidenced by the aforementioned parameters. Silencing NcoR1 or Ncor1 deficiency promoted both, parameters of inflammatory and oxidative stress such as Gclc, Gclm, Hmox1, and Ccl2, et, al. in AML12 cells and primary mouse hepatocytes, while NcoR1 over-expression shows the opposite results. Further, IR treated NcoR1△Hep mice displayed increased phosphorylation of p65, an essential parameter of the NFB signaling pathway, a critical mediator of stress signals in hepatocytes. Gene silencing of p65 in primary hepatocytes increased NcoR1 expression, suggesting that NFkB/p65 signaling is a negative regulator of NcoR1 expression. Conclusion: Our results indicate that damage mediated activation of NFB/p65 signaling decreases NcoR1 expression in hepatocytes, which is required for IR aggravation.
2025-05-10 | GSE296317 | GEO