SIRT1-NF-κB Axis as Therapeutic Target: History
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Inflammation is an adaptive response triggered by harmful conditions or stimuli, such as an infection or tissue damage pursuing homeostasis reestablishment. Liver diseases cause approximately 2 million deaths per year worldwide and hepatic inflammation is a common factor to all of them, being the main driver of hepatic tissue damage and causing progression from NAFLD (non-alcoholic fatty liver disease) to NASH (non-alcoholic steatohepatitis), cirrhosis and, ultimately, HCC (hepatocellular carcinoma). The metabolic sensor SIRT1, a class III histone deacetylase with strong expression in metabolic tissues such as liver, and transcription factor NF-κB, a master regulator of inflammatory response, show an antagonistic relationship in controlling inflammation. For this reason, SIRT1 targeting is emerging as a potential strategy to improve different metabolic and/or inflammatory pathologies. In this review, we explore diverse upstream regulators and some natural/synthetic activators of SIRT1 as possible therapeutic treatment for liver diseases.

  • cathepsin
  • inflammation
  • sirtuin-1
  • liver disease
  • NF-kB

SIRT1 in NF-κB Mediated Inflammation

Inflammation is an adaptive response aimed at restoring homeostasis altered by harmful stimuli, such as infection or tissue damage [35]. During the inflammatory response, several phases develop, starting with an initial pro-inflammatory phase, passing through the adaptive phase and ending with the reinstatement of homeostasis [35]. The switch between the pro-inflammatory and adaptive phase requires a metabolic change from an anabolic state to a catabolic state that depends on the sensing of adenosine monophosphate (AMP) and NAD+ levels by AMP-activated protein kinase (AMPK) and sirtuins, respectively. In this way, AMPK and sirtuins are able to couple inflammation and metabolism with chromatin state and gene transcription [36].
The nuclear factor kappa B (NF-κB) is a family of inducible transcription factors present in numerous cell types and integrated by seven different members, which form homo and heterodimers: NF-κB1 (p105 and p50), NF-κB2 (p100 and p52), RelA (p65), RelB and c-Rel [37]. NF-κB is considered as a major regulator of the inflammatory response due to its ability to regulate the transcription of genes involved in the establishment of immune and inflammatory response [37,38]. Its regulation occurs at several levels and, to date, three ways have been identified for NF-κB activation: (1) the canonical one, triggered mainly by cytokines such as TNF-α or IL1, and by toll-like receptor (TLR) agonists; (2) the non-canonical one, with an important function in B lymphocytes and (3) the activation induced by DNA damage [39,40]. A second level of regulation is post-translational modifications of NF-κB subunits, carried out by various proteins, including the IκB kinase (IKK) complex. Some of these modifications include processes of phosphorylation, acetylation, ubiquitination and prolyl isomerization, which regulates NF-κB activity by modulating its nuclear translocation, DNA binding, transactivation and interaction with CBP/p300-interacting transactivator 1 [41].
In quiescent cells, NF-κB is located in the cytoplasm, associated with inhibitory proteins (IκB-α, IκB-β, IκB-γ, IκBNS, Bcl-3) and some precursor proteins such as p100 and p105 (which, once cleaved, give rise to p52 and p50 subunits, respectively) [40]. In the canonical activation pathway, upon arrival of a stimulus to the cell, a phosphorylation occurs, followed by ubiquitination and degradation of its inhibitory proteins, in a proteasome dependent-manner. This releases NF-κB, which is then translocated to the nucleus, where it functions by activating gene transcription [42].
Both, NF-κB and SIRT1 signaling pathways are evolutionarily conserved mechanisms for the maintenance of homeostasis and whose interaction allows energy balance to be coupled with the immune/inflammatory response [43]. However, the nature of this relationship is antagonistic, so that SIRT1 is capable of inhibiting NF-κB signaling, and vice versa. This antagonism is explained based on two reasons. On the one hand, the body needs to adapt the metabolism to a rapid energy generation system that allows it to respond quickly to a harmful stimulus (such as an infection or tissue damage). On the other hand, it is necessary to re-establish homeostasis conditions once the harmful stimulus has disappeared [43]. Failure to resolve the inflammation would lead to a chronic inflammatory condition, typical of chronic liver diseases [44].
A direct association between SIRT1 and RelA/p65 subunit of NF-κB has been described: SIRT1 is able to deacetylate lysine 310 of RelA/p65 subunit, affecting its transcriptional activity and decreasing expression of its anti-apoptotic and pro-inflammatory target genes [45]. Additionally, deacetylation of RelA/p65 at lysine 310 facilitates methylation at lysines 314 and 315, which is important for the ubiquitination and degradation of RelA/p65 [46,47]. The different acetylations/ deacetylations of RelA/p65 can have various effects on NF-κB regulation but, particularly, deacetylation of RelA/p65 by SIRT1 favors the association of p65/p50 complex (the most abundant heterodimer of NF-κB [39,46,47]) with IκB-α (an inhibitor of NF-κB). This association triggers the transport of the NF-κB complex from the nucleus back to the cytoplasm and, therefore, inactivates the activity of NF-κB [48]. Furthermore, several authors have observed the possibility of forming complexes between PGC1-α/PPARs and NF-κB, enhanced by SIRT1, triggering repressive effects on the development of the inflammatory response (reviewed by Kauppinen et al. [43]).
Interestingly, a possible regulatory action of NF-κB on SIRT1 has also been suggested, since regions flanking the SIRT1 gene, both in mice and humans, contain numerous NF-κB binding elements [49,50]. In fact, some authors have already described this possible interaction. For example, Yamakuchi et al. [51] showed that the microRNA 34a (miR-34a) inhibits the expression of SIRT1 by binding to its 3′ UTR region; and Li et al. [52] described the mechanism by which NF-κB, through binding to the promoter region of miR-34a, is able to increase its level of expression. It should be noted that another miR-34a-controlled gene is AXL, a tyrosine kinase receptor that our group has implicated in the development of liver fibrosis [53], particularly in experimental NASH models and patients [54]. A link between AXL expression and SIRT1 has recently been reported in tissue macrophages [55] and may provide new targets for clinical treatment. Whether SIRT1/AXL can act in a coordinated manner and play a role in the progression of chronic liver disease is an aspect that deserves further studies.
Moreover, some factors, as oxidative stress or interferon γ (IFN-γ), can also suppress SIRT1 transcription or activity [52,56,57]. At the same time, NF-κB could induce oxidative stress through the enhancement of expression of ROS generating enzymes, such as NADPH oxidase (NOX) [58,59]. Additionally, it seems that NF-κB could interact with IFN-γ promoter [60]. Similarly, another study demonstrated that another microRNA, miR-378, is a key player in modulating NASH via TNF-α signaling. In particular, miR-378 acts as an important component of the molecular circuit composed by miR-378, AMPK, SIRT1, NF-κB and TNF-α to induce spontaneous activation of inflammatory genes with potential implications in NASH pathogenesis [61].
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This entry is adapted from the peer-reviewed paper 10.3390/ijms21113858

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