DONG Kaixuan, ZHENG Ya, WANG Yuping, GUO Qinghong. Mechanism of SIRT2 in Metabolic Dysfunction-associated Steatotic Liver Disease[J]. Medical Journal of Peking Union Medical College Hospital, 2024, 15(6): 1382-1388. DOI: 10.12290/xhyxzz.2024-0103
Citation: DONG Kaixuan, ZHENG Ya, WANG Yuping, GUO Qinghong. Mechanism of SIRT2 in Metabolic Dysfunction-associated Steatotic Liver Disease[J]. Medical Journal of Peking Union Medical College Hospital, 2024, 15(6): 1382-1388. DOI: 10.12290/xhyxzz.2024-0103

Mechanism of SIRT2 in Metabolic Dysfunction-associated Steatotic Liver Disease

Funds: 

Gansu Province Joint Scientific Research Fund Major Project 23JRRA1487

More Information
  • Corresponding author:

    GUO Qinghong, E-mail: gqh@lzu.edu.cn

  • Received Date: February 19, 2024
  • Accepted Date: April 09, 2024
  • Available Online: May 10, 2024
  • Publish Date: May 09, 2024
  • Issue Publish Date: November 29, 2024
  • Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by abnormal lipid deposition in the liver and its mechanism is closely related to insulin resistance, lipid metabolism disorders, oxidative stress, and abnormalities of the gut-liver axis. Currently, there is no effective treatment for this disease. Silent information regulator 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase which performs various pathophysiological functions by interacting with different substrates. For example, it is involved in improving metabolic homeostasis, alleviating liver inflammation, promoting liver regeneration, and delaying the progression of MASLD. In this paper, we present a review of the mechanism of action of SIRT2 in MASLD to analyze the potential value of SIRT2 as a therapeutic target in MASLD.

  • [1]
    Manikat R, Ahmed A, Kim D. Up-to-date global epidemiology of nonalcoholic fatty liver disease[J]. Hepatobiliary Surg Nutr, 2023, 12(6): 956-959. DOI: 10.21037/hbsn-23-548
    [2]
    Rinella M E, Lazarus J V, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature[J]. J Hepatol, 2023, 79(6): 1542-1556. DOI: 10.1016/j.jhep.2023.06.003
    [3]
    Staufer K, Stauber R E. Steatotic liver disease: metabolic dysfunction, alcohol, or both?[J]. Biomedicines, 2023, 11(8): 2108. DOI: 10.3390/biomedicines11082108
    [4]
    Branković M, Dukić M, Gmizić T, et al. New therapeutic approaches for the treatment of patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and increased cardiovascular risk[J]. Diagnostics (Basel), 2024, 14(2): 229. DOI: 10.3390/diagnostics14020229
    [5]
    Afzaal A, Rehman K, Kamal S, et al. Versatile role of sirtuins in metabolic disorders: from modulation of mitochon-drial function to therapeutic interventions[J]. J Biochem Mol Toxicol, 2022, 36(7): e23047. DOI: 10.1002/jbt.23047
    [6]
    Li B Y, Peng W Q, Liu Y, et al. HIGD1A links SIRT1 activity to adipose browning by inhibiting the ROS/DNA damage pathway[J]. Cell Rep, 2023, 42(7): 112731. DOI: 10.1016/j.celrep.2023.112731
    [7]
    Lin L S, Guo Z Y, He E J, et al. SIRT2 regulates extracellular vesicle-mediated liver-bone communication[J]. Nat Metab, 2023, 5(5): 821-841. DOI: 10.1038/s42255-023-00803-0
    [8]
    Wang Y, Yang J Q, Hong T T, et al. SIRT2: controversy and multiple roles in disease and physiology[J]. Ageing Res Rev, 2019, 55: 100961. DOI: 10.1016/j.arr.2019.100961
    [9]
    Leal H, Cardoso J, Valério P, et al. SIRT2 deficiency exacerbates hepatic steatosis via a putative role of the ER stress pathway[J]. Int J Mol Sci, 2022, 23(12): 6790. DOI: 10.3390/ijms23126790
    [10]
    Imai S, Armstrong C M, Kaeberlein M, et al. Transcrip-tional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase[J]. Nature, 2000, 403(6771): 795-800. DOI: 10.1038/35001622
    [11]
    Aventaggiato M, Vernucci E, Barreca F, et al. Sirtuins' control of autophagy and mitophagy in cancer[J]. Pharmacol Ther, 2021, 221: 107748. DOI: 10.1016/j.pharmthera.2020.107748
    [12]
    Zhang T C, Wang L N, Duan X P, et al. Sirtuins mediate mitochondrial quality control mechanisms: a novel thera-peutic target for osteoporosis[J]. Front Endocrinol (Lausanne), 2023, 14: 1281213.
    [13]
    Kim Y, Kang B E, Gariani K, et al. Loss of hepatic Sirt7 accelerates diethylnitrosamine (DEN)-induced formation of hepatocellular carcinoma by impairing DNA damage repair[J]. BMB Rep, 2024, 57(2): 98-103. DOI: 10.5483/BMBRep.2023-0187
    [14]
    Wei W X, Li T, Chen J L, et al. SIRT3/6: an amazing challenge and opportunity in the fight against fibrosis and aging[J]. Cell Mol Life Sci, 2024, 81(1): 69. DOI: 10.1007/s00018-023-05093-z
    [15]
    Vaquero A, Scher M B, Lee D H, et al. SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis[J]. Genes Dev, 2006, 20(10): 1256-1261. DOI: 10.1101/gad.1412706
    [16]
    Carmona B, Marinho H S, Matos C L, et al. Tubulin post-translational modifications: the elusive roles of acetylation[J]. Biology (Basel), 2023, 12(4): 561.
    [17]
    师艳红, 刘玉玲, 任凯利, 等. 人SIRT2基因结构和功能的生物信息分析及原核表达[J]. 生物化工, 2023, 9(6): 10-16. DOI: 10.3969/j.issn.2096-0387.2023.06.003

    Shi Y H, Liu Y L, Ren K L, et al. Bioinformatics analysis on structure and function of human silent information regulator 2 gene and its prokaryotic expression[J]. Biol Chem Eng, 2023, 9(6): 10-16. DOI: 10.3969/j.issn.2096-0387.2023.06.003
    [18]
    朱蕊, 武幸濡, 邸杰, 等. SIRT2去乙酰化酶活性位点突变体的构建及活性鉴定[J]. 生物技术, 2023, 33(2): 135-142.

    Zhu R, Wu X R, Di J, et al. Plasmid construction and deacetylase activity detection of SIRT2 enzyme mutants[J]. Biotechnology, 2023, 33(2): 135-142.
    [19]
    Yang S, Yang G Y, Wang X Y, et al. SIRT2 alleviated renal fibrosis by deacetylating SMAD2 and SMAD3 in renal tubular epithelial cells[J]. Cell Death Dis, 2023, 14(9): 646. DOI: 10.1038/s41419-023-06169-1
    [20]
    Li S, Guo L. The role of sirtuin 2 in liver-AN extensive and complex biological process[J]. Life Sci, 2024, 339: 122431. DOI: 10.1016/j.lfs.2024.122431
    [21]
    Piracha Z Z, Saeed U, Piracha I E, et al. Decoding the multifaceted interventions between human sirtuin 2 and dynamic hepatitis B viral proteins to confirm their roles in HBV replication[J]. Front Cell Infect Microbiol, 2023, 13: 1234903.
    [22]
    Park S, Chung M J, Son J Y, et al. The role of sirtuin 2 in sustaining functional integrity of the liver[J]. Life Sci, 2021, 285: 119997. DOI: 10.1016/j.lfs.2021.119997
    [23]
    Boström P, Wu J, Jedrychowski M P, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis[J]. Nature, 2012, 481(7382): 463-468. DOI: 10.1038/nature10777
    [24]
    Zineldeen D H, Tahoon N M, Sarhan N I. AICAR ameliorates non-alcoholic fatty liver disease via modulation of the HGF/NF-κB/SNARK signaling pathway and restores mitochondrial and endoplasmic reticular impairments in high-fat diet-fed rats[J]. Int J Mol Sci, 2023, 24(4): 3367. DOI: 10.3390/ijms24043367
    [25]
    Russo G L, Russo M, Ungaro P. AMP-activated protein kinase: a target for old drugs against diabetes and cancer[J]. Biochem Pharmacol, 2013, 86(3): 339-350. DOI: 10.1016/j.bcp.2013.05.023
    [26]
    Li D J, Sun S J, Fu J T, et al. NAD+-boosting therapy alleviates nonalcoholic fatty liver disease via stimulating a novel exerkine Fndc5/irisin[J]. Theranostics, 2021, 11(9): 4381-4402. DOI: 10.7150/thno.53652
    [27]
    Jung I, Koo D J, Lee W Y. Insulin resistance, non-alcoholic fatty liver disease and type 2 diabetes mellitus: clinical and experimental perspective[J]. Diabetes Metab J, 2024, 48(3): 327-339. DOI: 10.4093/dmj.2023.0350
    [28]
    Zeng P, Cai X S, Yu X Z, et al. Markers of insulin resistance associated with non-alcoholic fatty liver disease in non-diabetic population[J]. Sci Rep, 2023, 13(1): 20470. DOI: 10.1038/s41598-023-47269-4
    [29]
    Manning B D, Toker A. AKT/PKB signaling: navigating the network[J]. Cell, 2017, 169(3): 381-405. DOI: 10.1016/j.cell.2017.04.001
    [30]
    Ramakrishnan G, Davaakhuu G, Kaplun L, et al. Sirt2 deacetylase is a novel AKT binding partner critical for AKT activation by insulin[J]. J Biol Chem, 2014, 289(9): 6054-6066. DOI: 10.1074/jbc.M113.537266
    [31]
    Lantier L, Williams A S, Hughey C C, et al. SIRT2 knockout exacerbates insulin resistance in high fat-fed mice[J]. PLoS One, 2018, 13(12): e0208634. DOI: 10.1371/journal.pone.0208634
    [32]
    Dong T, Hu G G, Fan Z Q, et al. Activation of GPR3-β-arrestin2-PKM2 pathway in Kupffer cells stimulates glycolysis and inhibits obesity and liver pathogenesis[J]. Nat Commun, 2024, 15(1): 807. DOI: 10.1038/s41467-024-45167-5
    [33]
    Park J M, Kim T H, Jo S H, et al. Acetylation of glucokinase regulatory protein decreases glucose metabolism by suppressing glucokinase activity[J]. Sci Rep, 2015, 5: 17395. DOI: 10.1038/srep17395
    [34]
    Watanabe H, Inaba Y, Kimura K, et al. Sirt2 facilitates hepatic glucose uptake by deacetylating glucokinase regulatory protein[J]. Nat Commun, 2018, 9(1): 30. DOI: 10.1038/s41467-017-02537-6
    [35]
    Ren Y R, Ye Y L, Feng Y, et al. SL010110, a lead compound, inhibits gluconeogenesis via SIRT2-p300-mediated PEPCK1 degradation and improves glucose homeostasis in diabetic mice[J]. Acta Pharmacol Sin, 2021, 42(11): 1834-1846. DOI: 10.1038/s41401-020-00609-w
    [36]
    Zhang M M, Pan Y D, Dorfman R G, et al. Sirtinol promotes PEPCK1 degradation and inhibits gluconeogenesis by inhibiting deacetylase SIRT2[J]. Sci Rep, 2017, 7(1): 7. DOI: 10.1038/s41598-017-00035-9
    [37]
    Nie T, Wang X, Li A, et al. The promotion of fatty acid β-oxidation by hesperidin via activating SIRT1/PGC1α to improve NAFLD induced by a high-fat diet[J]. Food Funct, 2024, 15(1): 372-386. DOI: 10.1039/D3FO04348G
    [38]
    Shen W Y, Wan X Y, Hou J H, et al. Peroxisome proliferator-activated receptor γ coactivator 1α maintains NAD+ bioavailability protecting against steatohepatitis[J]. Life Med, 2022, 1(2): 207-220. DOI: 10.1093/lifemedi/lnac031
    [39]
    Krishnan J, Danzer C, Simka T, et al. Dietary obesity-associated Hif1α activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system[J]. Genes Dev, 2012, 26(3): 259-270. DOI: 10.1101/gad.180406.111
    [40]
    Helsley R N, Park S H, Vekaria H J, et al. Ketohexoki-nase-C regulates global protein acetylation to decrease carnitine palmitoyltransferase 1a-mediated fatty acid oxidation[J]. J Hepatol, 2023, 79(1): 25-42. DOI: 10.1016/j.jhep.2023.02.010
    [41]
    Ren H H, Hu F Q, Wang D, et al. Sirtuin 2 prevents liver steatosis and metabolic disorders by deacetylation of hepatocyte nuclear factor 4α[J]. Hepatology, 2021, 74(2): 723-740. DOI: 10.1002/hep.31773
    [42]
    Guo X Y, Yin X Z, Liu Z J, et al. Non-alcoholic fatty liver disease (NAFLD) pathogenesis and natural products for prevention and treatment[J]. Int J Mol Sci, 2022, 23(24): 15489. DOI: 10.3390/ijms232415489
    [43]
    Lin R T, Tao R, Gao X, et al. Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth[J]. Mol Cell, 2013, 51(4): 506-518. DOI: 10.1016/j.molcel.2013.07.002
    [44]
    Guo L, Guo Y Y, Li B Y, et al. Enhanced acetylation of ATP-citrate lyase promotes the progression of nonalcoholic fatty liver disease[J]. J Biol Chem, 2019, 294(31): 11805-11816. DOI: 10.1074/jbc.RA119.008708
    [45]
    Vallianou N, Christodoulatos G S, Karampela I, et al. Understanding the role of the gut microbiome and microbial metabolites in non-alcoholic fatty liver disease: current evidence and perspectives[J]. Biomolecules, 2021, 12(1): 56. DOI: 10.3390/biom12010056
    [46]
    Cornejo-Pareja I, Amiar M R, Ocaña-Wilhelmi L, et al. Non-alcoholic fatty liver disease in patients with morbid obesity: the gut microbiota axis as a potential pathophysiology mechanism[J]. J Gastroenterol, 2024, 59(4): 329-341. DOI: 10.1007/s00535-023-02075-7
    [47]
    Li X Y, Du Y M, Xue C Y, et al. SIRT2 deficiency aggravates diet-induced nonalcoholic fatty liver disease through modulating gut microbiota and metabolites[J]. Int J Mol Sci, 2023, 24(10): 8970. DOI: 10.3390/ijms24108970
    [48]
    Wen J J, Li M Z, Gao H, et al. Polysaccharides from fermented Momordica charantia L. with Lactobacillus plantarum NCU116 ameliorate metabolic disorders and gut microbiota change in obese rats[J]. Food Funct, 2021, 12(6): 2617-2630. DOI: 10.1039/D0FO02600J
    [49]
    Li W, Cao T, Luo C Y, et al. Crosstalk between ER stress, NLRP3 inflammasome, and inflammation[J]. Appl Microbiol Biotechnol, 2020, 104(14): 6129-6140. DOI: 10.1007/s00253-020-10614-y
    [50]
    Flamment M, Kammoun H L, Hainault I, et al. Endoplasmic reticulum stress: a new actor in the development of hepatic steatosis[J]. Curr Opin Lipidol, 2010, 21(3): 239-246. DOI: 10.1097/MOL.0b013e3283395e5c
    [51]
    Hong S H, Hong Y, Lee M J, et al. Natural product skatole ameliorates lipotoxicity-induced multiple hepatic damage under hyperlipidemic conditions in hepatocytes[J]. Nutrients, 2023, 15(6): 1490. DOI: 10.3390/nu15061490
    [52]
    DeZwaan-McCabe D, Sheldon R D, Gorecki M C, et al. ER stress inhibits liver fatty acid oxidation while unmitigated stress leads to anorexia-induced lipolysis and both liver and kidney steatosis[J]. Cell Rep, 2017, 19(9): 1794-1806. DOI: 10.1016/j.celrep.2017.05.020
    [53]
    Schuster S, Cabrera D, Arrese M, et al. Triggering and resolution of inflammation in NASH[J]. Nat Rev Gastroenterol Hepatol, 2018, 15(6): 349-364. DOI: 10.1038/s41575-018-0009-6
    [54]
    Zhang Y Q, Anoopkumar-Dukie S, Davey A K. SIRT1 and SIRT2 modulators: potential anti-inflammatory treatment for depression?[J]. Biomolecules, 2021, 11(3): 353. DOI: 10.3390/biom11030353
    [55]
    Yuan F, Xu Z M, Lu L Y, et al. SIRT2 inhibition exacerbates neuroinflammation and blood-brain barrier disruption in experimental traumatic brain injury by enhancing NF-κB p65 acetylation and activation[J]. J Neurochem, 2016, 136(3): 581-593. DOI: 10.1111/jnc.13423
    [56]
    Rothgiesser K M, Erener S, Waibel S, et al. Correction: SIRT2 regulates NF-κB-dependent gene expression through deacetylation of p65 Lys310[J]. J Cell Sci, 2019, 132(8): jcs232801. DOI: 10.1242/jcs.232801
    [57]
    He M, Chiang H H, Luo H Z, et al. An acetylation switch of the NLRP3 inflammasome regulates aging-associated chronic inflammation and insulin resistance[J]. Cell Metab, 2020, 31(3): 580-591. e5. DOI: 10.1016/j.cmet.2020.01.009
    [58]
    Zhang B L, Xu D, She L L, et al. Silybin inhibits NLRP3 inflammasome assembly through the NAD+/SIRT2 pathway in mice with nonalcoholic fatty liver disease[J]. FASEB J, 2018, 32(2): 757-767. DOI: 10.1096/fj.201700602R
    [59]
    Zhang R, Xu D, Zhang Y R, et al. Silybin restored CYP3A expression through the sirtuin 2/nuclear factor κ-B pathway in mouse nonalcoholic fatty liver disease[J]. Drug Metab Dispos, 2021, 49(9): 770-779. DOI: 10.1124/dmd.121.000438

Catalog

    Article Metrics

    Article views (163) PDF downloads (25) Cited by()
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return
    x Close Forever Close