The NAMPT/SIRT7/SOD2 axis regulates alveolar progenitor cell renewal and pulmonary fibrosis [bulkRNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE295740 | GEO | 2026/03/30
REPOSITORIES: GEO
Dataset's files
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Project description:We employed single-cell RNA sequencing using the 10x Genomics platform to investigate the role of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in NAD+ biosynthesis, in AT2 cells in the lung. NAMPT has been implicated in regulating stem cell function, mitochondrial bioenergetics, apoptosis, and senescence in neurodegenerative diseases, endothelial cells, and human iPS cells. Single-cell lung suspensions were prepared from Nampt AT2 conditional knockout and control mice at day 0 and day 4 post-bleomycin injury. scRNA-seq was performed on FACS-sorted Epcam+ and CD45+ live cells, and purified cells were clustered to evaluate NAMPT function in AT2 and immune cells.
2026-03-30 | GSE295739 | GEO
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
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.
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Project description:Molecular clocks in the periphery coordinate tissue-specific daily biorhythms by integrating input from the hypothalamic master clock and intracellular metabolic signals. One such key metabolic signal is the cellular concentration of NAD+, which oscillates along with its biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT). NAD+ levels feed back into the clock to influence rhythmicity of biological functions, yet whether this metabolic fine-tuning occurs ubiquitously across cell types and is a core clock feature is unknown. Here we show that NAMPT-dependent control over the molecular clock varies substantially between tissues. Brown adipose tissue (BAT) requires NAMPT to sustain the amplitude of the core clock, whereas rhythmicity in white adipose tissue (WAT) is only moderately dependent on NAD+ biosynthesis and the skeletal muscle clock is completely refractory to loss of NAMPT. In BAT and WAT, NAMPT differentially orchestrates oscillation of clock-controlled gene networks and the diurnality of metabolite levels. NAMPT coordinates the rhythmicity of TCA cycle intermediates in BAT, but not WAT, and loss of NAD+ abolishes these oscillations similarly to high fat diet (HFD)-induced circadian disruption. Adipose NAMPT depletion also improved the ability of animals to defend body temperature during cold stress but this is independent of time-of-day. Thus, our findings reveal that peripheral molecular clocks and metabolic biorhythms are shaped in a highly tissue-specific manner by NAMPT-dependent NAD+ synthesis.
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Project description:Drugs targeting mutant oncogenes are effective, even though resistance rapidly develops. This complex picture includes acquired intrinsic tumor and tumor microenvironmental -mediated mechanisms. Here we showed that melanoma cells resistant to BRAF inhibitors (BRAFi) overexpressed the rate limiting enzymes involved in nicotinamide (NAM) metabolism nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide N-methyltransferase (NNMT). Importantly, NAMPT and NNMT are released by these cells, both in the free-form or loaded in extracellular vesicles (EVs). NAMPT is emerging as mediator of BRAFi resistance in melanoma, but to date mainly associated with its role as main NAD-biosynthetic enzyme. It had been previously identified as soluble factor, but never in EVs released from melanoma cells, which highlights an impact on the tumor microenvironment (TME). NNMT was revealed increased in melanoma compared to benign nevi, however we showed for the first time its overexpression in resistant cells at intracellular and extracellular levels (present in secretome and in EVs). NNMT increased in BRAF-mutated patients linking its expression with the BRAF oncogenic signaling and correlates positively with pro-inflammatory signaling, immune cell migration and chemokine-mediated signaling pathways opening to a future deeper exploration of its functional role. Lastly, we proposed a tetrameric NNMT:TLR4 binding model offering a plausible structural and mechanistic basis for their association. Overall, the identification of NAMPT and, surprisingly also NNMT, included in EVs and abundantly released from resistant melanoma cells supports the impact of these moonlighting proteins involved in nicotinamide metabolism as mediators of BRAF/MEK inhibitors resistance with tumor intrinsic and potentially tumor microenvironment-mediated mechanisms. Interfering with nicotinamide metabolism could be a valid strategy to counteract drug resistance acting on the multifactorial tumor-host interactions.
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Project description:Nicotinamide adenine dinucleotide (NAD+) is a universal coenzyme regulating cellular energy metabolism in many cell types. Recent studies have demonstrated the close relationships between defective NAD+ metabolism and aging and age-associated metabolic diseases. The major purpose of the present study was to test the hypothesis that NAD+ biosynthesis, mediated by a rate-limiting NAD+ biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT), is essential for maintaining normal adipose tissue function and whole-body metabolic health during the aging process. To this end, we provided in-depth and comprehensive metabolic assessments for female adipocyte-specific Nampt knockout (ANKO) mice during aging. We first evaluated body fat mass in young (≤ 4-month-old), middle aged (10 to 14-month-old), and old (≥ 18-month-old) mice. Intriguingly, adipocyte-specific Nampt deletion protected against age-induced obesity without changing energy balance. However, data obtained from the hyperinsulinemic euglycemic clamp procedure demonstrated that, despite the lean phenotype, old ANKO mice had severe insulin resistance in skeletal muscle, heart, and white adipose tissue (WAT). Old ANKO mice also exhibited hyperinsulinemia and hypoadiponectinemia. Mechanistically, loss of Nampt caused marked decreases in WAT gene expression of lipogenic targets of peroxisome proliferator-activated receptor gamma (PPARγ) in an age-dependent manner. In addition, administration of a PPARγ agonist rosiglitazone restored fat mass and improved metabolic abnormalities in old ANKO mice. In conclusion, these findings highlight the importance of the NAMPT-NAD+-PPARγ axis in maintaining functional integrity and quantity of adipose tissue, and whole-body metabolic function in female mice during aging.
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