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Hepatocyte-specific knockout of Nicotinamide phosphoribosyltransferase increases susceptibility for liver fibrosis in mice

ABSTRACT: Hepatocyte-specific knockout of Nicotinamide phosphoribosyltransferase increases susceptibility for liver fibrosis in mice

PROVIDER: PRJNA603664 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10983700_1.fastq.gz	Fastqsanger.gz
	SRR10983700_2.fastq.gz	Fastqsanger.gz
	SRR10983701_1.fastq.gz	Fastqsanger.gz
	SRR10983701_2.fastq.gz	Fastqsanger.gz
	SRR10983702_1.fastq.gz	Fastqsanger.gz

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Hepatocyte-specific knockout of Nicotinamide phosphoribosyltransferase increases susceptibility for liver fibrosis in mice

Project description:We investigated the plasma and liver proteome changes in liver fibrosis in mice induced by hepatocyte-specific knockout of nicotinamide phosphoribosyltransferase (Nampt) upon a low-methionine, choline-free 60% high-fat (MCD) diet at multiple time points. We also investigated whether supplementation with nicotinamide riboside could alleviate liver injury and how the liver proteome changes upon NR supplementation.

2021-11-04 | PXD017170 | Pride

Hepatocyte-specific knockout of Nicotinamide phosphoribosyltransferase increases susceptibility for liver fibrosis in mice

Project description:Nicotinamide adenine dinucleotide (NAD+) supplementation has been suggested as a therapy against non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). We investigated whether hepatocyte-specific knockout of nicotinamide phosphoribosyltransferase (Nampt) caused increased susceptibility towards liver damage in mice fed a low-methionine, choline-free 60% high-fat (MCD) diet. Knockout mice (HNKO) accumulated less hepatic triglyceride than WT littermates after 3 weeks of MCD, but had increased scores for liver inflammation, necrosis, and fibrosis. We found that fibrosis, necrosis, and portal inflammation was also present in HNKO mice on a purified control diet (PD) but not in chow-fed HNKO mice due to a higher content of NAD+ precursors in the diet. The PD induced fibrosis within 3 days of exposure could be prevented by supplementation with the NAD+ precursor nicotinamide riboside (NR). When NR was supplied after fibrosis induction, hepatic NAD+ levels markedly increased, and portal inflammation was attenuated. The fibrosis phenotype was associated with a decreased abundance of proteins involved in oxidation and reduction processes, particularly for proteins in oxidative phosphorylation (OXPHOS). NR supplementation increased abundance of these proteins. High-resolution respirometry revealed that PD-fed HNKO mice had decreased oxygen consumption when stimulated with succinate, and a decrease in maximal uncoupled respiratory capacity. Conclusions: We show that HNKO mice have increased susceptibility towards liver fibrosis when dietary NAD+ content is restricted, and that low NAD+ levels can affect hepatic mitochondrial function. Furthermore, our data suggest NR treatment has potential for preventing liver damage and NASH progression.

2021-11-03 | GSE144443 | GEO

Extracellular Nicotinamide Phosphoribosyltransferase (eNAMPT) boosts IFNγ-induced macrophage polarization

Project description:Extracellular Nicotinamide Phosphoribosyltransferase (eNAMPT) boosts IFNγ-induced macrophage polarization

| PRJNA781578 | ENA

The role of nicotinamide phosphoribosyltransferase (Nampt) in hippocampal neural stem/progenitor cells

Project description:Neural stem/progenitor cell (NSPC) proliferation and self-renewal, as well as insult-induced differentiation, decrease markedly with age, but the molecular mechanisms responsible for these declines remain unclear. Here we show that levels of NAD+ and nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in mammalian NAD+ biosynthesis, decrease with age in the hippocampus. Ablation of Nampt in adult NSPCs reduced their pool and proliferation in vivo. The decrease in the NSPC pool during aging can be rescued by enhancing hippocampal NAD+ levels. Nampt is the main source of NSPC NAD+ levels and required for G1/S progression of the NSPC cell cycle. Nampt is also critical for oligodendrocytic lineage fate decisions through a mechanism mediated redundantly by Sirt1 and Sirt2. Ablation of Nampt in the adult NSPCs in vivo reduced NSPC-mediated oligodendrogenesis upon injury. These phenotypes recapitulate defects in NSPCs during aging, implicating Nampt-mediated NAD+ biosynthesis as a mediator of these age-associated functional declines. Total RNA obtained from neurospheres derived from postnatal hippocampi subjected to 48 hours in vitro of incubation with Nampt-specific inhibitor FK866 (10 nM, 4 samples) or vehicle (DMSO, 1:1000, 4 samples).

2014-05-08 | E-GEOD-49784 | biostudies-arrayexpress

Extracellular Nicotinamide Phosphoribosyltransferase (eNAMPT) boosts IFNγ-induced macrophage polarization

Project description:Nicotinamide phosphoribosyltransferase (NAMPT), alongside being a crucial enzyme to synthesize NAD in cells, has also been shown to be a secreted protein (eNAMPT). In this respect, this protein is found increased in plasma of cancer patients as well as in patients suffering from immune-mediated disorders and preclinical models have demonstrated that it is involved in their pathogenesis (e.g. (inflammatory bowel disease). In the present contribution, we evaluated the effect of this protein on macrophages performing a comprehensive RNAseq analysis, coupled to functional assays. Using peritoneal exudate cells (PECs), we now report that eNAMPT has chemoattractive and M1-skewing properties in macrophages and this holds true also in human monocyte-derived macrophages. Furthermore, we report that this protein is able to boost the responses to IFNγ, and this is likely to be mediated by STAT1-STAT3-activation. Importantly, IFNγ triggers the upregulation and secretion of eNAMPT, thereby providing evidence of a positive feedback loop upon cytokine activation. Last, we report that these phenomena are not a result of TLR4 activation, the only eNAMPT receptor that has been recognised until now, prompting the knowledge that other receptors may be involved.

2021-11-20 | GSE189104 | GEO

The role of nicotinamide phosphoribosyltransferase (Nampt) in hippocampal neural stem/progenitor cells

2014-05-08 | GSE49784 | GEO

Novel Protective Role of Nicotinamide Phosphoribosyltransferase in Acetaminophen-induced Acute Liver Injury in Mice

Project description:Acetaminophen overdose is the most common cause of acute liver injury (ALI) or acute liver failure in the USA. Its pathogenetic mechanisms are incompletely understood. Additional studies are warranted to identify new genetic risk factors for more mechanistic insights and new therapeutic target discoveries. The objective of this study was to explore the role and mechanisms of nicotinamide phosphoribosyltransferase (NAMPT) in acetaminophen-induced ALI. C57BL/6 Nampt gene wild type (Nampt+/+)-, heterozygous knockout (Nampt+/-)-, and overexpression (NamptOE)-mice were treated with overdose of acetaminophen, followed by histological, biochemical, and transcriptomic evaluation of liver injury. The mechanism of Nampt in acetaminophen -induced hepatocytic toxicity was also explored in cultured primary hepatocytes. Three lines of evidence have convergently demonstrated that acetaminophen overdose triggers the most severe oxidative stress and necrosis, and the highest expression of key necrosis driving genes in Nampt+/- mice, while the effects in NamptOE mice were least severe relative to Nampt+/+ mice. These findings support that NAMPT protects against acetaminophen induced ALI.

2018-04-03 | GSE110787 | GEO

Extracellular Nicotinamide Phosphoribosyltransferase neutralisation harnesses T cell responses in breast cancer by repressing the PD-1/PD-L1 axis

Project description:Nicotinamide phosphoribosyltransferase (NAMPT) is a key intracellular enzyme that particulates in NAD homeostasis but is also a released cytokine (eNAMPT) that is found elevated in inflammatory conditions and in cancer. Given that in breast cancer patients, eNAMPT has been found elevated and its levels correlate with prognosis and staging, we set to investigate the effect of its neutralization with a specific monoclonal antibody. Neutralization of eNAMPT with C269 led to a decreased tumour size and reduced number of metastases. RNAseq and functional assays showed that eNAMPT controlled the PD-L1/PD-1 axis and its neutralization led to a restoration of antitumoural immune responses. These studies are highly consistent with eNAMPT as a novel immunotherapeutic target for triple negative breast cancer.

2023-01-30 | GSE223539 | GEO

Extracellular Nicotinamide Phosphoribosyltransferase (eNAMPT) Drives Abnormal Pericyte-Rich Vasculature in Triple-Negative Breast Cancer

Project description:Extracellular Nicotinamide Phosphoribosyltransferase (eNAMPT) Drives Abnormal Pericyte-Rich Vasculature in Triple-Negative Breast Cancer

| PRJNA1163376 | ENA

Novel Protective Role of Nicotinamide Phosphoribosyltransferase in Acetaminophen-induced Acute Liver Injury in Mice

Project description:Novel Protective Role of Nicotinamide Phosphoribosyltransferase in Acetaminophen-induced Acute Liver Injury in Mice

| PRJNA434562 | ENA