NAD(+)-dependent SIRT1 Deacetylase Participates in Epigenetic Reprogramming during Endotoxin Tolerance

Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 03/2011; 286(11):9856-64. DOI: 10.1074/jbc.M110.196790
Source: PubMed


Gene-selective epigenetic reprogramming and shifts in cellular bioenergetics develop when Toll-like receptors (TLR) recognize
and respond to systemic life-threatening infections. Using a human monocyte cell model of endotoxin tolerance and human leukocytes
from acute systemic inflammation with sepsis, we report that energy sensor sirtuin 1 (SIRT1) coordinates the epigenetic and
bioenergy shifts. After TLR4 signaling, SIRT1 rapidly accumulated at the promoters of TNF-α and IL-1β, but not IκBα; SIRT1
promoter binding was dependent on its co-factor, NAD+. During this initial process, SIRT1 deacetylated RelA/p65 lysine 310 and nucleosomal histone H4 lysine 16 to promote termination
of NFκB-dependent transcription. SIRT1 then remained promoter bound and recruited de novo induced RelB, which directed assembly of the mature transcription repressor complex that generates endotoxin tolerance. SIRT1
also promoted de novo expression of RelB. During sustained endotoxin tolerance, nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting
enzyme for endogenous production of NAD+, and SIRT1 expression increased. The elevation of SIRT1 required protein stabilization and enhanced translation. To support
the coordination of bioenergetics in human sepsis, we observed elevated NAD+ levels concomitant with SIRT1 and RelB accumulation at the TNF-α promoter of endotoxin tolerant sepsis blood leukocytes.
We conclude that TLR4 stimulation and human sepsis activate pathways that couple NAD+ and its sensor SIRT1 with epigenetic reprogramming.

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Available from: Charles E Mccall, Aug 29, 2015
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    • "The shift in NAD+ availability and decreased ATP availability during the transition from hyperinflammation to adaptation is the key to understanding the role of sirtuins in sepsis[83]. Increase in nuclear NAD+ activates SIRT1, which promotes gene silencing facultative heterochromatin formation at the promotors of proinflammatory genes such as TNF-í µí»¼ and IL-1í µí»½[30,84]. Mechanistically, activated SIRT1 first directly binds and deactivates NF-í µí¼…B RelA/p65 through deacetylation and proteasome degradation[85]. "
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    ABSTRACT: Sirtuins (SIRT), first discovered in yeast as NAD+ dependent epigenetic and metabolic regulators, have comparable activities in human physiology and disease. Mounting evidence supports that the seven-member mammalian sirtuin family (SIRT1–7) guard homeostasis by sensing bioenergy needs and responding by making alterations in the cell nutrients. Sirtuins play a critical role in restoring homeostasis during stress responses. Inflammation is designed to “defend and mend” against the invading organisms. Emerging evidence supports that metabolism and bioenergy reprogramming direct the sequential course of inflammation; failure of homeostasis retrieval results in many chronic and acute inflammatory diseases. Anabolic glycolysis quickly induced (compared to oxidative phosphorylation) for ROS and ATP generation is needed for immune activation to “defend” against invading microorganisms. Lipolysis/fatty acid oxidation, essential for cellular protection/hibernation and cell survival in order to “mend,” leads to immune repression. Acute/chronic inflammations are linked to altered glycolysis and fatty acid oxidation, at least in part, by NAD+ dependent function of sirtuins. Therapeutically targeting sirtuins may provide a new class of inflammation and immune regulators. This review discusses how sirtuins integrate metabolism, bioenergetics, and immunity during inflammation and how sirtuin-directed treatment improves outcome in chronic inflammatory diseases and in the extreme stress response of sepsis.
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    • "This means that Nampt promotes osteogenic differentiation through an SIRT1- mediated pathway (Li et al., 2013). This pathway is also implicated in epigenetic reprogramming associated with endotoxin tolerance – SIRT1 activated by NAD + (controlled by Nampt) causes chromatin shifts, resulting in the initiation of endotoxin tolerance during sepsis (Liu et al., 2011). As previously mentioned, substantial amounts of visfatin are expressed in the placenta during pregnancy (Morgan et al., 2008 "
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    • "Emerging evidence indicates that the SIRT family of NAD + sensors is critically involved in linking metabolism and inflammation (Liu et al., 2012a; Liu et al., 2011; Yeung et al., 2004). The increased NAD + levels brought about by the Nampt salvage pathway in mammalian cells activate SIRT1 to deacetylate and inactivate NF-kB p65, thereby terminating inflammatory responses (Liu et al., 2011; Yeung et al., 2004). Aside from the "
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    ABSTRACT: The orphan nuclear receptor estrogen-related receptor α (ERRα; NR3B1) is a key metabolic regulator, but its function in regulating inflammation remains largely unknown. Here, we demonstrate that ERRα negatively regulates Toll-like receptor (TLR)-induced inflammation by promoting Tnfaip3 transcription and fine-tuning of metabolic reprogramming in macrophages. ERRα-deficient (Esrra(-/-)) mice showed increased susceptibility to endotoxin-induced septic shock, leading to more severe pro-inflammatory responses than control mice. ERRα regulated macrophage inflammatory responses by directly binding the promoter region of Tnfaip3, a deubiquitinating enzyme in TLR signaling. In addition, Esrra(-/-) macrophages showed an increased glycolysis, but impaired mitochondrial respiratory function and biogenesis. Further, ERRα was required for the regulation of NF-κB signaling by controlling p65 acetylation via maintenance of NAD(+) levels and sirtuin 1 activation. These findings unravel a previously unappreciated role for ERRα as a negative regulator of TLR-induced inflammatory responses through inducing Tnfaip3 transcription and controlling the metabolic reprogramming. Copyright © 2015 Elsevier Inc. All rights reserved.
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