Substrate-Dependent Sensitivity of SIRT1 to Nicotinamide Inhibition

Rymarchyk, Stacia; Kang, Wenjia; Cen, Yana

doi:10.3390/biom11020312

Cited by 9 publications

(4 citation statements)

References 63 publications

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“…Furthermore, gastric acids are not expelled into the duodenum after DJB, which increases the pH of duodenal content. The deacetylation activity of SIRT1 is pH-dependent, and higher pH attenuates the inhibition of SIRT1 by nicotinamide[ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Duodenal-jejunal bypass increases intraduodenal bile acids and upregulates duodenal SIRT1 expression in high-fat diet and streptozotocin-induced diabetic rats

Han¹,

Liu²,

Zhang³

et al. 2022

WJG

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BACKGROUND The mechanisms underlying diabetes remission after duodenal-jejunal bypass (DJB) remain elusive. In DJB surgery, the duodenum is excluded. However, the duodenum has emerged as an important regulator of glucose homeostasis, and elevated duodenal SIRT1 leads to improved hepatic insulin sensitivity. After DJB, bile acids (BAs) in the duodenum are not mixed and diluted by the ingested food. And activation of BA receptors promotes SIRT1 expression in many tissues. We hypothesized that BA-mediated upregulation of SIRT1 may contribute to diabetic control after DJB. AIM To investigate the surgical effects of DJB on duodenal SIRT1 expression and uncover the potential crosslinks between BAs and SIRT1. METHODS Twenty diabetic rats were randomly allocated to the sham ( n = 10) and DJB ( n = 10) groups. Body weight, food intake, fasting blood glucose (FBG), serum and intraduodenal total BA (TBA) levels were measured accordingly. Oral glucose tolerance test (OGTT) and intraperitoneal pyruvate tolerance test (ipPTT) were performed to evaluate the effects of surgeries on systemic glucose disposal and hepatic gluconeogenesis. The key genes of BA signaling pathway in the duodenal mucosa, including farnesoid X receptor (FXR), small heterodimer partner (SHP), and Takeda G-protein-coupled receptor 5 (TGR5) were evaluated by real-time quantitative polymerase chain reaction 8 wk postoperatively. The duodenal SIRT1, AMPK, and phosphorylated AMPK (p-AMPK) levels were evaluated by western blotting. Rat small intestine epithelial IEC-6 cells were treated with GW4064 and INT-777 to verify the effects of BAs on SIRT1 expression in enterocytes. RESULTS The DJB group exhibited body weight and food intake comparable to those of the sham group at all postoperative time points. The FBG level and area under the curve for the OGTT and ipPTT were significantly lower in the DJB group. The DJB group exhibited higher fasting and postprandial serum TBA levels than the sham group at both 2 and 8 wk postoperatively. At 8 wk after surgery, the DJB group showed higher intraluminal TBA concentration, upregulated mRNA expression of FXR and SHP, and elevated protein expression of SIRT1 and p-AMPK in the descending and horizontal segments of the duodenum. Activation of FXR and TGR5 receptors by GW4064 and INT-777 increased the mRNA and protein expression of SIRT1 and promoted the phosphorylation of AMPK in IEC-6 cells. CONCLUSION DJB elevates intraduodenal BA levels and activates the duodenal BA signaling pathway, which may upregulate duodenal SIRT1 and further contribute to improved glucose homeostasis after DJB.

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Section: Discussionmentioning

confidence: 99%

Duodenal-jejunal bypass increases intraduodenal bile acids and upregulates duodenal SIRT1 expression in high-fat diet and streptozotocin-induced diabetic rats

Han¹,

Liu²,

Zhang³

et al. 2022

WJG

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“…Unlike NMN and NR, NAM can inhibit sirtuins, a class of proteins linked to NAD+ benefits. [90,91]. Additionally, NAM conversion to NAD+ has inherent limitations.…”

Section: Efficacy and Therapeutic Applications Of Nad+ Boosting Strat...mentioning

confidence: 99%

Nicotinamide Mononucleotide: Deciphering Metabolic Complexities for Improved Health Outcomes

Benjamin,

Crews

2024

Preprint

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Nicotinamide mononucleotide (NMN), a key NAD+ precursor, exhibits distinct metabolic characteristics and potential health benefits. Recent investigations underscore the pivotal role of gut bacteria and specialized uptake mechanisms in NMN metabolism. While human trials demonstrate NMN's safety and promising health outcomes, challenges persist. Variability in results is likely influenced by lifestyle, health conditions, and individual genetic and gut microbiota differences. Understanding how these factors affect NMN metabolism is crucial for personalized approaches and maximizing NMN's potential. Advances in delivery systems show promise for enhancing NMN bioavailability, but further understanding of optimal NAD+ levels and reliable measures of NMN's effects is necessary. This comprehensive approach is key to optimizing NMN's impact on human health and longevity.

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“…2) and measured the RNA levels by RT-qPCR. We treated cells with trichostatin A (TSA), an inhibitor of class I, II, IV, histone deacetylases (HDACs) [57], nicotinamide (NAM) [58], an inhibitor of class III HDACs (sirtuins), or PJ34, an inhibitor of Poly (ADPribose) polymerase-1 (PARP-1) [59][60][61]. These treatments were performed either in presence or absence of 5-Aza-dC (Aza), an inhibitor of DNA methylation [57].…”

Section: The Frg2 Promoter Is Activated By Inhibition Of Histone Acet...mentioning

confidence: 99%

Post-transcriptional RNA stabilization of telomere-proximal RNAs FRG2, DBET, D4Z4 at human 4q35 in response to genotoxic stress and D4Z4 macrosatellite repeat length

Salsi,

Losi,

Salani

et al. 2024

Preprint

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Background: Reduced copy number of the D4Z4 macrosatellite at human chromosome 4q35 is associated with facioscapulohumeral muscular dystrophy (FSHD). A pervasive idea is that chromatin alterations at the 4q35 locus following D4Z4 repeat unit deletion lead to disease via inappropriate expression of nearby genes. Here, we sought to analyze transcription and chromatin characteristics across 4q35 and how these are affected by D4Z4 deletions and exogenous stresses. Results: We found that the 4q subtelomere is subdivided into discrete domains, each with characteristic chromatin features associated with distinct gene expression profiles. Centromere-proximal genes within 4q35 (ANT1, FAT1 and FRG1) display active histone marks at their promoters. In contrast, poised or repressed markings are present at telomere-proximal loci including FRG2, DBE-T and D4Z4. We discovered that these discrete domains undergo region-specific chromatin changes upon treatment with chromatin enzyme inhibitors or genotoxic drugs. We demonstrated that the 4q35 telomere-proximal FRG2, DBE-T and D4Z4-derived transcripts are induced upon DNA damage to levels inversely correlated with the D4Z4 repeat number, are stabilized through post-transcriptional mechanisms upon DNA damage, and are bound to chromatin. Conclusion: Our study reveals unforeseen biochemical features of RNAs from clustered transcription units within the 4q35 subtelomere. Specifically, the FRG2, DBE-T and D4Z4-derived transcripts are chromatin-associated and are stabilized post-transcriptionally after induction by genotoxic stress. Remarkably, the extent of this response is modulated by the copy number of the D4Z4 repeats, raising new hypotheses about their regulation and function in human biology and disease.

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Substrate-Dependent Sensitivity of SIRT1 to Nicotinamide Inhibition

Cited by 9 publications

References 63 publications

Duodenal-jejunal bypass increases intraduodenal bile acids and upregulates duodenal SIRT1 expression in high-fat diet and streptozotocin-induced diabetic rats

Duodenal-jejunal bypass increases intraduodenal bile acids and upregulates duodenal SIRT1 expression in high-fat diet and streptozotocin-induced diabetic rats

Nicotinamide Mononucleotide: Deciphering Metabolic Complexities for Improved Health Outcomes

Post-transcriptional RNA stabilization of telomere-proximal RNAs FRG2, DBET, D4Z4 at human 4q35 in response to genotoxic stress and D4Z4 macrosatellite repeat length

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