Sirtuin-1 is a nutrient-dependent modulator of inflammation

Kotas, Maya E.; Gorecki, Michelle C.; Gillum, Matthew P.

doi:10.4161/adip.23437

Cited by 43 publications

(41 citation statements)

References 47 publications

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“…Enhanced HUR may promote the stability of numerous target mRNAs, including that encoding SIRT1, via association of HUR with the 3 0 -untranslated region of Sirt1 mRNA, that promotes its stability and thus a rise in Sirt1 expression (Newsholme & de Bittencourt 2014). In turn, SIRT1 enhances the expression of the main heat shock factor, HSF1, and heat shock elements (HSEs) in the nuclei, resulting in expression of HSP70 (Kotas et al 2013, Cruzat et al 2014a, Petry et al 2014, as observed herein (Fig. 5B).…”

Section: Discussionsupporting

confidence: 49%

“…5B). In contrast, SIRT1 can suppress inflammation and stimulate HSP responses; however, in response to chronic inflammation, similar to that in obesity-associated diabetes, the SIRT1/HUR axis is repressed (Kotas et al 2013), contributing to the unresolved inflammation (LafontaineLacasse et al 2011, Luu et al 2013. In this study, using our in vitro model to mimic in vivo inflammation, we observed that Ala-Gln maintained the HSP70 levels via the SIRT1/HUR axis.…”

Section: Discussionmentioning

confidence: 53%

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Alanyl-glutamine improves pancreatic β-cell function following ex vivo inflammatory challenge

Cruzat¹,

Keane²,

Scheinpflug³

et al. 2014

Journal of Endocrinology

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Obesity-associated diabetes and concomitant inflammation may compromise pancreatic b-cell integrity and function. L-glutamine and L-alanine are potent insulin secretagogues, with antioxidant and cytoprotective properties. Herein, we studied whether the dipeptide L-alanyl-L-glutamine (Ala-Gln) could exert protective effects via sirtuin 1/HUR (SIRT1/HUR) signalling in b-cells, against detrimental responses following ex vivo stimulation with inflammatory mediators derived from macrophages (IMMs). The macrophages were derived from blood obtained from obese subjects. Macrophages were exposed (or not) to lipopolysaccharide (LPS) to generate a pro-inflammatory cytokine cocktail. The cytokine profile was determined following analysis by flow cytometry. Insulin-secreting BRIN-BD11 b-cells were exposed to IMMs and then cultured with or without Ala-Gln for 24 h. Chronic insulin secretion, the L-glutamineglutathione (GSH) axis, and the level of insulin receptor b (IR-b), heat shock protein 70 (HSP70), SIRT1/HUR, CCAAT-enhancer-binding protein homologous protein (CHOP) and cytochrome c oxidase IV (COX IV) were evaluated. Concentrations of cytokines, including interleukin 1b (IL1b), IL6, IL10 and tumour necrosis factor alpha (TNFa) in the IMMs, were higher following exposure to LPS. Subsequently, when b-cells were exposed to IMMs, chronic insulin secretion, and IR-b and COX IV levels were decreased, but these effects were partially or fully attenuated by the addition of Ala-Gln. The glutamine-GSH axis and HSP70 levels, which were compromised by IMMs, were also restored by Ala-Gln, possibly due to protection of SIRT1/HUR levels, and a reduction of CHOP expression. Using an ex vivo inflammatory approach, we have demonstrated Ala-Gln-dependent b-cell protection mediated by coordinated effects on the glutamine-GSH axis, and the HSP pathway, maintenance of mitochondrial metabolism and stimulus-secretion coupling essential for insulin release.

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Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 53%

Alanyl-glutamine improves pancreatic β-cell function following ex vivo inflammatory challenge

Cruzat¹,

Keane²,

Scheinpflug³

et al. 2014

Journal of Endocrinology

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“…However, in those studies it is difficult to discern whether the observed beneficial effects on glucose metabolism are due to direct activation of SIRT1 in skeletal muscle or if they are due to effects of SIRT1 activation in other important metabolic tissues such as adipose tissue, pancreas, or liver. Indeed, activation of SIRT1 specifically in adipose tissue (23), ␤-cells (8,27), or liver (24, 46) of HFD-fed rodents has been shown to improve glucose homeostasis. Furthermore, improvements in glucose tolerance have been reported in a mouse model with moderate overexpression of SIRT1 in brain and adipose tissue but not in skeletal muscle, suggesting that effects in these other tissues, but not in skeletal muscle, play a role in the metabolic benefits of SIRT1 activation (7).…”

Section: Discussionmentioning

confidence: 99%

High-fat diet-induced impairment of skeletal muscle insulin sensitivity is not prevented by SIRT1 overexpression

White

Philp

Fridolfsson

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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expression is reduced under insulin-resistant conditions, such as those resulting from high-fat diet (HFD) feeding and obesity. Herein, we investigated whether constitutive activation of SIRT1 in skeletal muscle prevents HFD-induced muscle insulin resistance. To address this, mice with muscle-specific overexpression of SIRT1 (mOX) and wild-type (WT) littermates were fed a control diet (10% calories from fat) or HFD (60% of calories from fat) for 12 wk. Magnetic resonance imaging and indirect calorimetry were used to measure body composition and energy expenditure, respectively. Whole body glucose metabolism was assessed by oral glucose tolerance test, and insulinstimulated glucose uptake was measured at a physiological insulin concentration in isolated soleus and extensor digitorum longus muscles. Although SIRT1 was significantly overexpressed in muscle of mOX vs. WT mice, body weight and percent body fat were similarly increased by HFD for both genotypes, and energy expenditure was unaffected by diet or genotype. Importantly, impairments in glucose tolerance and insulin-mediated activation of glucose uptake in skeletal muscle that occurred with HFD feeding were not prevented in mOX mice. In contrast, mOX mice showed enhanced postischemic cardiac functional recovery compared with WT mice, confirming the physiological functionality of the SIRT1 transgene in this mouse model. Together, these results demonstrate that activation of SIRT1 in skeletal muscle alone does not prevent HFD-induced glucose intolerance, weight gain, or insulin resistance. SIRT1; insulin resistance; high-fat diet; skeletal muscle IMPAIRED GLUCOSE UPTAKE in response to insulin is a common metabolic derangement that can result from the consumption of a hypercaloric, high-fat diet (HFD) and is a key contributor to the etiology of type 2 diabetes (6, 30). The NAD ϩ -dependent protein deacetylase sirtuin 1 (SIRT1) may be a key convergence point that links fluctuations in nutrient status to the regulation of insulin sensitivity (18). Mechanistically, this occurs via deacetylation of acetylated targets by SIRT1, which in turn regulates their cellular localization and function (45).Supporting its possible role as an energy sensor in skeletal muscle, SIRT1 activity has been shown to increase in low nutrient conditions (38) and to decrease in insulin-resistant states such as those present in patients with type 2 diabetes and with HFD feeding (17, 40). Thus, interventions that activate SIRT1 hold promise for the treatment of insulin resistance and type 2 diabetes (18, 21). Indeed, SIRT1 activation with small molecule activators (16,25,26,39) or via increasing NAD ϩ availability (3, 4, 12, 44) improves glucose homeostasis in models of insulin resistance.To investigate the role of SIRT1 activation in vivo, several genetic mouse models have been created and have revealed metabolic benefits of SIRT1 overexpression. For example, mice with moderate SIRT1 overexpression in several important metabolic tissues, including white adipose tissue, brown adipose tissu...

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“…SIRT1 is able to de-acetylate many different transcription factors in the nucleus such as p53, NF-B, myogenic differentiation, high mobility group I, E2F transcription factor, and forkhead box O, thus playing an essential role in cell differentiation, cell survival, tumorigenesis, inflammation, and metabolism (27)(28)(29)(30)(31). Moreover, SIRT1 targets chromatin (histones) as well as nonchromatin proteins in the cells, has been linked to transcriptional silencing, and appears to play a key role in inflammation (32,33). More recently, several reports have shown that normal cartilage homeostasis requires enzymatically active SIRT1 protein in vivo (34 -36).…”

Section: Mesenchymal Stem Cells (Mscs)mentioning

confidence: 99%

Sirtuin-1 (SIRT1) Is Required for Promoting Chondrogenic Differentiation of Mesenchymal Stem Cells

Buhrmann

Busch

Shayan

et al. 2014

Journal of Biological Chemistry

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Background: Molecular signaling during chondrogenic differentiation of mesenchymal stem cells (MSC) is poorly understood. Results: Knockdown of sirtuin-1 (SIRT1) in MSC induced inhibition of chondrogenesis, Sox9 expression, up-regulation of nuclear factor-B (NF-B) phosphorylation and acetylation, and NF-B-dependent pro-inflammatory enzymes. Conclusion: SIRT1 supports chondrogenic differentiation of MSCs by Sox9 activation and NF-B deacetylation. Significance: These findings may be essential for improving cartilage tissue regeneration.

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Sirtuin-1 is a nutrient-dependent modulator of inflammation

Cited by 43 publications

References 47 publications

Alanyl-glutamine improves pancreatic β-cell function following ex vivo inflammatory challenge

Alanyl-glutamine improves pancreatic β-cell function following ex vivo inflammatory challenge

High-fat diet-induced impairment of skeletal muscle insulin sensitivity is not prevented by SIRT1 overexpression

Sirtuin-1 (SIRT1) Is Required for Promoting Chondrogenic Differentiation of Mesenchymal Stem Cells

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