SIRT1-NF-κB Axis as Therapeutic Target: Comparison
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Please note this is a comparison between Version 2 by Rita Xu and Version 1 by Montserrat Mari.

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

Inflammation is an adaptive response aimed at restoring homeostasis altered by harmful stimuli, such as infection or tissue damage [1]. 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 [1]. 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].

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 [2].

 

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 [3]. 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 [3][4]. 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 [5][6]. 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 [7].

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) [6]. 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 [8].

 

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 [9]. 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 [9]. Failure to resolve the inflammation would lead to a chronic inflammatory condition, typical of chronic liver diseases [10].

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].

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 [11]. 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 [12][13]. 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 [5][12][13]) 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 . 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. [9]).

 

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 [14][15]. In fact, some authors have already described this possible interaction. For example, Yamakuchi et al. [16] showed that the microRNA 34a (miR-34a) inhibits the expression of SIRT1 by binding to its 3′ UTR region; and Li et al. [17] 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 [18], particularly in experimental NASH models and patients [19]. A link between AXL expression and SIRT1 has recently been reported in tissue macrophages [20] 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.

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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  • 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]
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  • 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]

Moreover, some factors, as oxidative stress or interferon γ (IFN-γ), can also suppress SIRT1 transcription or activity [17][21][22]. At the same time, NF-κB could induce oxidative stress through the enhancement of expression of ROS generating enzymes, such as NADPH oxidase (NOX) [23][24]. Additionally, it seems that NF-κB could interact with IFN-γ promoter [25]. 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 [26].

References

  1. Ruslan Medzhitov; Origin and physiological roles of inflammation. Nature 2008, 454, 428-435, 10.1038/nature07201.
  2. Zhiyong Zhang; Stephen F. Lowry; Leonard Guarente; Beatrice Haimovich; Roles of SIRT1 in the Acute and Restorative Phases following Induction of Inflammation*. Journal of Biological Chemistry 2010, 285, 41391-41401, 10.1074/jbc.M110.174482.
  3. He, G.; Karin, M; NF-kappaB and STAT3—Key players in liver inflammation and cancer. Cell Res. 2011, 21, 159–168.
  4. Liu, T.; Zhang, L.; Joo, D.; Sun, S.-C; NF-κB signaling in inflammation. Signal Transduct. Target Ther. 2017, 2, 17023.
  5. 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.
  6. Schmitz, M.L.; Mattioli, I.; Buss, H.; Kracht, M; NF-kappaB: A multifaceted transcription factor regulated at several levels. Chembiochem 2004, 5, 1348–1358.
  7. Luedde, T.; Schwabe, R.F; NF-kappaB in the liver—Linking injury, fibrosis and hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 2011, 8, 108–118.
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  9. Anu Kauppinen; Tiina Suuronen; Johanna Ojala; Kai Kaarniranta; Antero Salminen; Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cellular Signalling 2013, 25, 1939-1948, 10.1016/j.cellsig.2013.06.007.
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  11. 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.
  12. 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.
  13. 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.
  14. 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.
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  17. Munekazu Yamakuchi; Marcella Ferlito; Charles J. Lowenstein; miR-34a repression of SIRT1 regulates apoptosis. Proceedings of the National Academy of Sciences 2008, 105, 13421-13426, 10.1073/pnas.0801613105.
  18. Juan Li; Kai Wang; Xuedan Chen; Hui Meng; Min Song; Yan Wang; Xueqing Xu; Yun Bai; Transcriptional activation of microRNA-34a by NF-kappa B in human esophageal cancer cells. BMC Molecular Biology 2012, 13, 4-4, 10.1186/1471-2199-13-4.
  19. Cristina Bárcena; Milica Stefanovic; Anna Tutusaus; Leonel Joannas; Anghara Menendez; Carmen García-Ruiz; Pau Sancho-Bru; Montserrat Marí; Joan Caballería; Carla V Rothlin; et al.José C. FernándezchecaPablo Garcia De FrutosAlbert Morales Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation. Journal of Hepatology 2015, 63, 670-678, 10.1016/j.jhep.2015.04.013.
  20. Anna Tutusaus; Estefanía De Gregorio; Blanca Cucarull; Helena Cristóbal; Cristina Aresté; Isabel Graupera; Mar Coll; Anna Colell; Gro Gausdal; James B. Lorens; et al.Pablo García De FrutosAlbert MoralesMontserrat Marí A Functional Role of GAS6/TAM in Nonalcoholic Steatohepatitis Progression Implicates AXL as Therapeutic Target. Cellular and Molecular Gastroenterology and Hepatology 2020, 9, 349-368, 10.1016/j.jcmgh.2019.10.010.
  21. Samuel Caito; Saravanan Rajendrasozhan; Suzanne Cook; Sangwoon Chung; Hongwei Yao; Alan E. Friedman; Paul S. Brookes; Irfan Rahman; SIRT1 is a redox‐sensitive deacetylase that is post‐translationally modified by oxidants and carbonyl stress. The FASEB Journal 2010, 24, 3145-3159, 10.1096/fj.09-151308.
  22. Zhen Chen; Tzu-Pin Shentu; Liang Wen; David A. Johnson; John Y‐J Shyy; Regulation of SIRT1 by Oxidative Stress-Responsive miRNAs and a Systematic Approach to Identify Its Role in the Endothelium. Antioxidants & Redox Signaling 2013, 19, 1522-1538, 10.1089/ars.2012.4803.
  23. Ping Li; Yuhao Zhao; Xiaoyan Wu; Minjie Xia; Mingming Fang; Yasumasa Iwasaki; Jiahao Sha; Q. Chen; Yong Xu; Aiguo Shen; et al. Interferon gamma (IFN-γ) disrupts energy expenditure and metabolic homeostasis by suppressing SIRT1 transcription. Nucleic Acids Research 2011, 40, 1609-1620, 10.1093/nar/gkr984.
  24. Josef Anrather; Gianfranco Racchumi; Costantino Iadecola; NF-κB Regulates Phagocytic NADPH Oxidase by Inducing the Expression of gp91phox. Journal of Biological Chemistry 2006, 281, 5657-5667, 10.1074/jbc.m506172200.
  25. A Sica; L Dorman; V Viggiano; M Cippitelli; P Ghosh; N Rice; H A Young; Interaction of NF-kappaB and NFAT with the interferon-gamma promoter. Journal of Biological Chemistry 1997, 272, 30412–30420.
  26. Tianpeng Zhang; Junjie Hu; Xiaomei Wang; Xiaoling Zhao; Zhuoyu Li; Junqi Niu; Clifford J. Steer; Guohua Zheng; Guisheng Song; MicroRNA-378 promotes hepatic inflammation and fibrosis via modulation of the NF-κB-TNFα pathway.. Journal of Hepatology 2018, 70, 87-96, 10.1016/j.jhep.2018.08.026.
  27. Tianpeng Zhang; Junjie Hu; Xiaomei Wang; Xiaoling Zhao; Zhuoyu Li; Junqi Niu; Clifford J. Steer; Guohua Zheng; Guisheng Song; MicroRNA-378 promotes hepatic inflammation and fibrosis via modulation of the NF-κB-TNFα pathway.. Journal of Hepatology 2018, 70, 87-96, 10.1016/j.jhep.2018.08.026.
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