SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity

Yoshizaki, Takeshi; Schenk, Simon; Imamura, Teruhiko; Babendure, Jennie L.; Sonoda, Noriyuki; Bae, Eun Ju; Oh, Da Young; Lü, Min; Milne, Jill C.; Westphal, Christoph H.; Bandyopadhyay, Gautam; Olefsky, Jerrold M.

doi:10.1152/ajpendo.00417.2009

Cited by 371 publications

(321 citation statements)

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“…The results presented here show that SIRT1 represses LEF1 gene expression, which activates MMP13 gene expression. Studies have shown that SIRT1 can demonstrate a broad antiinflammatory function in a variety of tissues (44)(45)(46)(47)(48)(49). For example, in chronic obstructive pulmonary disorder, SIRT1 exerts a protective effect, partially because of its capacity to down-regulate MMP9 (49), and modulating NFkB activity during the disease (48).…”

Section: Sirt1 Represses Mmp13 Gene Expression 3123mentioning

confidence: 99%

LEF1‐mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes

et al. 2017

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Reduced SIRT1 activity and levels during osteoarthritis (OA) promote gradual loss of cartilage. Loss of cartilage matrix is accompanied by an increase in matrix metalloproteinase (MMP) 13, partially because of enhanced LEF1 transcriptional activity. In this study, we assessed the role of SIRT1 in LEF1-mediated MMP13 gene expression in human OA chondrocytes. Results showed that MMP13 protein levels and enzymatic activity decreased significantly during SIRT1 overexpression or activation by resveratrol. Conversely, MMP13 gene expression was reduced in chondrocytes transfected with SIRT1 siRNA or treated with nicotinamide (NAM), a sirtuin inhibitor. Chondrocytes challenged with IL-1b, a cytokine involved in OA pathogenesis, enhanced LEF1 protein levels and gene expression, resulting in increased MMP13 gene expression; however, overexpression of SIRT1 during IL-1b challenge impeded LEF1 levels and MMP13 gene expression. Previous reports showed that LEF1 binds to the MMP13 promoter and transactivates its expression, but we observed that SIRT1 repressed LEF1 protein and mRNA expression, ultimately reducing LEF1 transcriptional activity, as judged by luciferase assay. Finally, mouse articular cartilage from Sirt1 2/2 presented increased LEF1 and MMP13 protein levels, similar to human OA cartilage. Thus, demonstrating for the first time that SIRT1 represses MMP13 in human OA chondrocytes, which appears to be mediated, at least in part, through repression of the transcription factor LEF1, a known modulator of MMP13 gene expression.-Elayyan, J., Lee, E.-J., Gabay, O., Smith, C. A., Qiq, O., Reich, E., Mobasheri, A., Henrotin, Y., Kimber, S. J., Dvir-Ginzberg, M. LEF1-mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes. FASEB J. 31, 3116-3125 (2017). www.fasebj.orgArticular cartilage undergoes age-related degenerative changes leading to the joint disease osteoarthritis (OA). Gradual loss of hyaline joint cartilage during OA is evoked through chronic synovitis, which involves the accumulation of proinflammatory cytokines, as IL1b, TNF-a, and IL6 within the joint (1-5), subsequently leading to a steady increase in matrix metalloproteinases (MMPs) and a disintegrin and MMP with thrombospondin motifs (ADAMTS) proteins, which further promote cartilage destruction (6-12). Recent experimental attempts ABBREVIATIONS: ACAN, aggrecan gene; ADAMTS, a disintegrin and metalloproteinase with thrombospondin-like motifs; BMP, bone morphogenic protein; ChIP, chromatin immunoprecipitation; COL2A1, collagen-2 a-1 gene; FBS, fetal bovine serum; FGF, fibroblast growth factor; GDF, growth differentiation factor; GSK3b, glycogen synthase kinase-3b; hESC, human embryonic stem cell; KO, knockout; LEF, lymphoid enhancer factor; MMP, matrix metalloproteinase; NAM, nicotinamide adenine mononucleotide; OA, osteoarthritis; Res, resveratrol; qPCR, quantitative PCR; siRNA, small interfering RNA; SIRT1, silent mating type information regulation 2 homolog 1 (sirtuin-1); SOX9, sex-determining-region-on-the-Y-chromosome-relate...

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Section: Sirt1 Represses Mmp13 Gene Expression 3123mentioning

confidence: 99%

LEF1‐mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes

et al. 2017

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“…Similar to PARP-2 gene inactivation, SIRT1 activation has been shown to inhibit the production of inflammatory mediators and suppress certain forms of inflammation [92][93][94]. It is therefore plausible that the induction of SIRT1 may be responsible for the antiinflammatory effect of PARP-2 depletion in colitis [59] and in astrocyte activation [58] .…”

Section: Interaction With Sirt1mentioning

confidence: 99%

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Szántó

Brunyánszki

Kiss

et al. 2012

Cell. Mol. Life Sci.

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Abstract:Poly(ADP-ribose) polymerase (PARP)-2 is a nuclear enzyme that belongs to the PARP family and PARP-2 is responsible for 5-15% of total cellular PARP activity. PARP-2 was originally described in connection to DNA repair and in physiological and pathophysiological processes associated with genome maintenance (e.g. centromere and telomere protection, spermiogenesis, thymopoesis, azoospermia and tumorigenesis). Recent reports identified important rearrangements in gene expression upon the knockout of PARP-2. Such rearrangements heavily impact on inflammation and metabolism. Metabolic effects are mediated through modifying PPARg and SIRT1 function. Altered gene expression gives rise to a complex phenotype characterized primarily by enhanced mitochondrial activity that results both in beneficial (loss of fat, enhanced insulin sensitivity) and in disadvantageous (pancreatic beta cell hypofunction upon high fat feeding) consequences. Enhanced mitochondrial biogenesis provides protection in oxidative stress related diseases. Hereby, we review the recent developments in PARP-2 research with special attention to the involvement of PARP-2 in transcriptional and metabolic regulation. We would like to thank the referee for his/her efforts to further improve our manuscript.1. Page 2 -the modifications here are fairly minimalistic and the abbreviations ARTD2 and ARTD1 are not even defined. Powered by Editorial Manager® and Preprint Manager® from Aries Systems Corporationand ARTD1 are not even defined.In the corresponding section we incorporated the basic information on the newly proposed nomenclature in our previous version upon the suggestion of the Reviewer. We agree with the Reviewer that the appearance of the new nomenclature in our manuscript is important. Moreover, in the current version we added ARTD-2 as a keyword to help those future readers that follow the new nomenclature. The fact that ARTD1 is the equivalent of PARP-1 is defined in the chapter "PARP superfamily" second paragraph, first row. We added the abbreviation of ARDT-2 in the last sentence in the first paragraph of the chapter "The PARP superfamily". We think that these are sufficient for the understanding of the position of PARP-2 in the PARP/ARTD superfamily.We would like to note here, that the proposed new nomenclature did not gain ground in the scientific community yet. There are only 3 relevant papers on Medline for the keyword ARTD1, ARTD2 or ARTD (since 2010, the publication of the paper by In summary, we are confident that our review sufficiently takes the new nomenclature into consideration despite of the fact that it is not yet accepted by the scientific community. Sequence homology modeling was carried out by Ame and co-workers (Ame et al. Bioessays. 26:882-893. 2004). They classified sequences as PARPs on the basis of sequence homology, therefore sequence homology does exist. However, mutation(s) in a sequence does not necessarily mean that sequence homology is lost. In the incriminated text, mutations mean rather point mutations that aff...

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“…In skeletal muscle cells, PPAR/ agonism inhibited palmitate-induced ER stress and significantly decreased levels of pro-inflammatory cytokines, TNF and IL-6, in an AMPK dependent manner [90]. The inflammatory environment in T2DM could be abrogated by increased activity of PPAR/ target genes such as SIRT1 [91,92].…”

Section: Proteotoxic Stress In the Pathogenesis Of Diseases Not Formementioning

confidence: 99%

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

et al. 2015

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Cells have a number of mechanisms to maintain protein homeostasis, including proteasomemediated degradation of ubiquitinated proteins and autophagy, a regulated process of 'self-eating' where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by tolllike receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses.Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis.3 Cells must maintain a delicate balance between the demands for protein synthesis and the need to avoid accumulation of incompletely processed or unfolded proteins that can accumulate under normal conditions and even more so when cells face a variety of stresses. The unfolded protein response (UPR) is an evolutionarily conserved mechanism to maintain cellular homeostasis by preventing the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Disturbed protein folding in the ER is primarily detected by three transmembrane (TM) proteins: activating transcription factor 6 (ATF6), inositol-requiring transmembrane kinase/endonuclease 1 (IRE1) and pancreatic ER kinase (PERK). The combined action of these sensors reduces global protein synthesis while upregulating the production of chaperone proteins that can stabilize misfolded proteins. Apart from ER homeostasis, the UPR can modulate other biological functions, including apoptosis, protein secretion, and as we will discuss further, inflammatory responses [1,2].A series of molecular changes are initiated in response to cellular stressors in order to minimize damage caused by unfavorable environmental conditions, such as temperature changes, toxins (e.g. bacterial, chemical), radiation, mechanical damage, nutritional status as well as incompletely folded proteins intracellularly (Figure 1). The UPR serves the adaptive purpose of protecting the cell by activating a series of mechanisms including the induction of molecular chaperones to assist with correct folding -e.g. heat shock proteins and foldases. Interestingly there are a number of connections between the UPR and inflammatory signaling pat...

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SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity

Cited by 371 publications

References 40 publications

LEF1‐mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes

LEF1‐mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

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