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.
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].
- Medzhitov, R. Origin and physiological roles of inflammation. Nature 2008, 454, 428–435. [Google Scholar] [PubMed]
- Zhang, Z.; Lowry, S.F.; Guarente, L.; Haimovich, B. Roles of SIRT1 in the acute and restorative phases following induction of inflammation. J. Biol. Chem. 2010, 285, 41391–41401. [Google Scholar] [CrossRef]
- He, G.; Karin, M. NF-kappaB and STAT3—Key players in liver inflammation and cancer. Cell Res. 2011, 21, 159–168. [Google Scholar] [CrossRef]
- Liu, T.; Zhang, L.; Joo, D.; Sun, S.-C. NF-κB signaling in inflammation. Signal Transduct. Target Ther. 2017, 2, 17023. [Google Scholar] [CrossRef]
- Mitchell, J.P.; Carmody, R.J. Chapter Two—NF-κB and the Transcriptional Control of Inflammation. In Transcriptional Gene Regulation in Health and Disease; Loos, F., Ed.; Academic Press: Cambridge, MA, USA, 2018; pp. 41–84. [Google Scholar]
- Schmitz, M.L.; Mattioli, I.; Buss, H.; Kracht, M. NF-kappaB: A multifaceted transcription factor regulated at several levels. Chembiochem 2004, 5, 1348–1358. [Google Scholar] [CrossRef]
- Luedde, T.; Schwabe, R.F. NF-kappaB in the liver—Linking injury, fibrosis and hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 2011, 8, 108–118. [Google Scholar]
- Karin, M.; Ben-Neriah, Y. Phosphorylation Meets Ubiquitination: The Control of NF-κB Activity. Annu. Rev. Immunol. 2000, 18, 621–663. [Google Scholar] [CrossRef]
- Kauppinen, A.; Suuronen, T.; Ojala, J.; Kaarniranta, K.; Salminen, A. Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal. 2013, 25, 1939–1948. [Google Scholar] [PubMed]
- Del Campo, J.A.; Gallego, P.; Grande, L. Role of inflammatory response in liver diseases: Therapeutic strategies. World J. Hepatol. 2018, 10, 1–7. [Google Scholar] [CrossRef]
- Yeung, F.; Hoberg, J.E.; Ramsey, C.S.; Keller, M.D.; Jones, D.R.; Frye, R.A.; Mayo, M.W. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 2004, 23, 2369–2380. [Google Scholar] [CrossRef] [PubMed]
- Yang, X.-D.; Tajkhorshid, E.; Chen, L.-F. Functional Interplay between Acetylation and Methylation of the RelA Subunit of NF-κB. Mol. Cell Biol. 2010, 30, 2170–2180. [Google Scholar] [CrossRef] [PubMed]
- Rothgiesser, K.M.; Fey, M.; Hottiger, M.O. Acetylation of p65 at lysine 314 is important for late NF-kappaB-dependent gene expression. BMC Genom. 2010, 11, 22. [Google Scholar] [CrossRef] [PubMed]
- Dai, Y.; Rahmani, M.; Dent, P.; Grant, S. Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-kappaB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation. Mol. Cell Biol. 2005, 25, 5429–5444. [Google Scholar] [CrossRef] [PubMed]
- Mahlknecht, U.; Voelter-Mahlknecht, S. Chromosomal characterization and localization of the NAD+-dependent histone deacetylase gene sirtuin 1 in the mouse. Int. J. Mol. Med. 2009, 23, 245–252. [Google Scholar] [CrossRef]
- Voelter-Mahlknecht, S.; Mahlknecht, U. Cloning, chromosomal characterization and mapping of the NAD-dependent histone deacetylases gene sirtuin 1. Int. J. Mol. Med. 2006, 17, 59–67. [Google Scholar] [CrossRef]
- Yamakuchi, M.; Ferlito, M.; Lowenstein, C.J. miR-34a repression of SIRT1 regulates apoptosis. Proc. Natl. Acad. Sci. USA 2008, 105, 13421–13426. [Google Scholar] [CrossRef]
- Li, J.; Wang, K.; Chen, X.; Meng, H.; Song, M.; Wang, Y.; Xu, X.; Bai, Y. Transcriptional activation of microRNA-34a by NF-kappa B in human esophageal cancer cells. BMC Mol. Biol. 2012, 13, 4. [Google Scholar] [CrossRef]
- Bárcena, C.; Stefanovic, M.; Tutusaus, A.; Joannas, L.; Menéndez, A.; García-Ruiz, C.; Sancho-Bru, P.; Marí, M.; Caballeria, J.; Rothlin, C.V.; et al. Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation. J. Hepatol. 2015, 63, 670–678. [Google Scholar] [PubMed]
- Tutusaus, A.; de Gregorio, E.; Cucarull, B.; Cristóbal, H.; Aresté, C.; Graupera, I.; Coll, M.; Colell, A.; Gausdal, G.; Lorens, J.B.; et al. A Functional Role of GAS6/TAM in Nonalcoholic Steatohepatitis Progression Implicates AXL as Therapeutic Target. Cell Mol. Gastroenterol. Hepatol. 2020, 9, 349–368. [Google Scholar] [PubMed]
- McCubbrey, A.L.; Nelson, J.D.; Stolberg, V.R.; Blakely, P.K.; McCloskey, L.; Janssen, W.J.; Freeman, C.M.; Curtis, J.L. MicroRNA-34a Negatively Regulates Efferocytosis by Tissue Macrophages in Part via SIRT1. J. Immunol. 2016, 196, 1366–1375. [Google Scholar] [CrossRef] [PubMed]
- Caito, S.; Rajendrasozhan, S.; Cook, S.; Chung, S.; Yao, H.; Friedman, A.E.; Brookes, P.S.; Rahman, I. SIRT1 is a redox-sensitive deacetylase that is post-translationally modified by oxidants and carbonyl stress. FASEB J. 2010, 24, 3145–3159. [Google Scholar] [CrossRef]
- Chen, Z.; Shentu, T.P.; Wen, L.; Johnson, D.; Shyy, J. Regulation of SIRT1 by Oxidative Stress-Responsive miRNAs and A Systematic Approach to Identify Its Role in the Endothelium. Antioxid. Redox Signal. 2013, 19, 1522–1538. [Google Scholar] [CrossRef]
- Li, P.; Zhao, Y.; Wu, X.; Xia, M.; Fang, M.; Iwasaki, Y.; Sha, J.; Chen, Q.; Xu, Y.; Shen, A. Interferon gamma (IFN-γ) disrupts energy expenditure and metabolic homeostasis by suppressing SIRT1 transcription. Nucleic. Acids Res. 2012, 40, 1609–1620. [Google Scholar] [CrossRef]
- Anrather, J.; Racchumi, G.; Iadecola, C. NF-κB regulates phagocytic NADPH oxidase by inducing the expression of gp91phox. J. Biol. Chem. 2006, 281, 5657–5667. [Google Scholar] [CrossRef]
- Sica, A.; Dorman, L.; Viggiano, V.; Cippitelli, M.; Ghosh, P.; Rice, N.; Young, H.A. Interaction of NF-kappaB and NFAT with the interferon-gamma promoter. J. Biol. Chem. 1997, 272, 30412–30420. [Google Scholar] [CrossRef]
- Zhang, T.; Hu, J.; Wang, X.; Zhao, X.; Li, Z.; Niu, J.; Steer, C.J.; Zheng, G.; Song, G. MicroRNA-378 promotes hepatic inflammation and fibrosis via modulation of the NF-κB-TNFα pathway. J. Hepatol. 2019, 70, 87–96. [Google Scholar] [CrossRef]
This entry is adapted from the peer-reviewed paper 10.3390/ijms21113858