Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Research Article

Naphthofuran Derivative BF4, a New Potent SIRT1 Activator, Regulates Lipid Metabolism in 3T3-L1 Adipocytes via the SIRT1-AMPK Pathway

Author(s): Jian Gao, Fan Li, Ye Huang, Shihao Li and Qisi Lin*

Volume 19, Issue 9, 2023

Published on: 28 April, 2023

Page: [879 - 888] Pages: 10

DOI: 10.2174/1573406419666230330141501

Price: $65

Abstract

Aim: Our previously reported naphthofuran derivative BF4, identified as a potent silent information regulator 1 (SIRT1) activator, could alleviate high glucose stimulating apoptosis and inflammation response in human renal tubular epithelial (HK-2) cells.

Introduction: In this study, the underlying effects of BF4 on lipid metabolism in 3T3-L1 adipocytes were investigated.

Methods: The effects of BF4 on pre-adipocyte differentiation and adipocyte lipolysis were studied using oil red O staining and quantitative glycerol and triglyceride content assay kits. Moreover, the molecular mechanism of BF4 on adipogenesis and lipid metabolism in 3T3-L1 adipocytes was investigated by real-time quantitative PCR and Western blotting analysis.

Results: We found that compound BF4 significantly decreased adipogenesis and lipid accumulation and inhibited the differentiation of 3T3-L1 pre-adipocytes into adipocytes. Moreover, compound BF4 decreased the expressions of several key regulators in adipocyte differentiation, including C/EBPβ and PPARγ, and their downstream lipogenesis targets via the activation of the SIRT1/ AMPK pathway.

Conclusion: Our results demonstrated that the novel SIRT1 activator BF4 might be a potent candidate for regulating lipid metabolism.

Graphical Abstract

[1]
Langin, D. In and out: Adipose tissue lipid turnover in obesity and dyslipidemia. Cell Metab., 2011, 14(5), 569-570.
[http://dx.doi.org/10.1016/j.cmet.2011.10.003] [PMID: 22055498]
[2]
Sørensen, T.I.A. From fat cells through an obesity theory. Eur. J. Clin. Nutr., 2018, 72(10), 1329-1335.
[http://dx.doi.org/10.1038/s41430-018-0100-7] [PMID: 29535406]
[3]
Stephens, J.M.; Lee, J.; Pilch, P.F. Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. J. Biol. Chem., 1997, 272(2), 971-976.
[http://dx.doi.org/10.1074/jbc.272.2.971] [PMID: 8995390]
[4]
Camp, H.S.; Ren, D.; Leff, T. Adipogenesis and fat-cell function in obesity and diabetes. Trends Mol. Med., 2002, 8(9), 442-447.
[http://dx.doi.org/10.1016/S1471-4914(02)02396-1] [PMID: 12223316]
[5]
Jo, J.; Gavrilova, O.; Pack, S.; Jou, W.; Mullen, S.; Sumner, A.E.; Cushman, S.W.; Periwal, V. Hypertrophy and/or hyperplasia: Dynamics of adipose tissue growth. PLOS Comput. Biol., 2009, 5(3), e1000324.
[http://dx.doi.org/10.1371/journal.pcbi.1000324] [PMID: 19325873]
[6]
Frye, R.A. Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem. Biophys. Res. Commun., 1999, 260(1), 273-279.
[http://dx.doi.org/10.1006/bbrc.1999.0897] [PMID: 10381378]
[7]
Haigis, M.C.; Guarente, L.P. Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction. Genes Dev., 2006, 20(21), 2913-2921.
[http://dx.doi.org/10.1101/gad.1467506] [PMID: 17079682]
[8]
Elesela, S.; Morris, S.B.; Narayanan, S.; Kumar, S.; Lombard, D.B.; Lukacs, N.W. Sirtuin 1 regulates mitochondrial function and immune homeostasis in respiratory syncytial virus infected dendritic cells. PLoS Pathog., 2020, 16(2), e1008319.
[http://dx.doi.org/10.1371/journal.ppat.1008319] [PMID: 32106265]
[9]
Cohen, H.Y.; Miller, C.; Bitterman, K.J.; Wall, N.R.; Hekking, B.; Kessler, B.; Howitz, K.T.; Gorospe, M.; de Cabo, R.; Sinclair, D.A. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science, 2004, 305(5682), 390-392.
[http://dx.doi.org/10.1126/science.1099196] [PMID: 15205477]
[10]
Bonkowski, M.S.; Sinclair, D.A. Slowing ageing by design: The rise of NAD+ and sirtuin-activating compounds. Nat. Rev. Mol. Cell Biol., 2016, 17(11), 679-690.
[http://dx.doi.org/10.1038/nrm.2016.93] [PMID: 27552971]
[11]
Hubbard, B.P.; Sinclair, D.A. Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol. Sci., 2014, 35(3), 146-154.
[http://dx.doi.org/10.1016/j.tips.2013.12.004] [PMID: 24439680]
[12]
Lagouge, M.; Argmann, C.; Gerhart-Hines, Z.; Meziane, H.; Lerin, C.; Daussin, F.; Messadeq, N.; Milne, J.; Lambert, P.; Elliott, P.; Geny, B.; Laakso, M.; Puigserver, P.; Auwerx, J. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell, 2006, 127(6), 1109-1122.
[http://dx.doi.org/10.1016/j.cell.2006.11.013] [PMID: 17112576]
[13]
Baur, J.A.; Pearson, K.J.; Price, N.L.; Jamieson, H.A.; Lerin, C.; Kalra, A.; Prabhu, V.V.; Allard, J.S.; Lopez-Lluch, G.; Lewis, K.; Pistell, P.J.; Poosala, S.; Becker, K.G.; Boss, O.; Gwinn, D.; Wang, M.; Ramaswamy, S.; Fishbein, K.W.; Spencer, R.G.; Lakatta, E.G.; Le Couteur, D.; Shaw, R.J.; Navas, P.; Puigserver, P.; Ingram, D.K.; de Cabo, R.; Sinclair, D.A. Resveratrol improves health and survival of mice on a high-calorie diet. Nature, 2006, 444(7117), 337-342.
[http://dx.doi.org/10.1038/nature05354] [PMID: 17086191]
[14]
Milne, J.C.; Lambert, P.D.; Schenk, S.; Carney, D.P.; Smith, J.J.; Gagne, D.J.; Jin, L.; Boss, O.; Perni, R.B.; Vu, C.B.; Bemis, J.E.; Xie, R.; Disch, J.S.; Ng, P.Y.; Nunes, J.J.; Lynch, A.V.; Yang, H.; Galonek, H.; Israelian, K.; Choy, W.; Iffland, A.; Lavu, S.; Medvedik, O.; Sinclair, D.A.; Olefsky, J.M.; Jirousek, M.R.; Elliott, P.J.; Westphal, C.H. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature, 2007, 450(7170), 712-716.
[http://dx.doi.org/10.1038/nature06261] [PMID: 18046409]
[15]
Krueger, J.G.; Suárez-Fariñas, M.; Cueto, I.; Khacherian, A.; Matheson, R.; Parish, L.C.; Leonardi, C.; Shortino, D.; Gupta, A.; Haddad, J.; Vlasuk, G.P.; Jacobson, E.W.A. Randomized, placebo-controlled study of SRT2104, a SIRT1 Activator, in patients with moderate to severe psoriasis. PLoS One, 2015, 10(11), e0142081.
[http://dx.doi.org/10.1371/journal.pone.0142081] [PMID: 26556603]
[16]
Gao, J.; Chen, Q.Q.; Huang, Y.; Li, K.H.; Geng, X.J.; Wang, T.; Lin, Q.S.; Yao, R.S. Design, synthesis and pharmacological evaluation of naphthofuran derivatives as potent SIRT1 activators. Front. Pharmacol., 2021, 12, 653233.
[http://dx.doi.org/10.3389/fphar.2021.653233] [PMID: 33995069]
[17]
Chayaratanasin, P.; Caobi, A.; Suparpprom, C.; Saenset, S.; Pasukamonset, P.; Suanpairintr, N.; Barbieri, M.A.; Adisakwattana, S. Clitoria ternatea flower petal extract inhibits adipogenesis and lipid accumulation in 3T3-L1 preadipocytes by downregulating adipogenic gene expression. Molecules, 2019, 24(10), 1894.
[http://dx.doi.org/10.3390/molecules24101894] [PMID: 31108834]
[18]
Lasa, A.; Churruca, I.; Eseberri, I.; Andrés-Lacueva, C.; Portillo, M.P. Delipidating effect of resveratrol metabolites in 3T3-L1 adipocytes. Mol. Nutr. Food Res., 2012, 56(10), 1559-1568.
[http://dx.doi.org/10.1002/mnfr.201100772] [PMID: 22945685]
[19]
Kim, N.H.; Jegal, J.; Kim, Y.; Heo, J.D.; Rho, J.R.; Yang, M.; Jeong, E. Chokeberry extract and its active polyphenols suppress adipogenesis in 3T3-L1 adipocytes and modulates fat accumulation and insulin resistance in diet-induced obese mice. Nutrients, 2018, 10(11), 1734.
[http://dx.doi.org/10.3390/nu10111734] [PMID: 30424495]
[20]
Livak, K.J.; Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)). Method. Methods, 2001, 25(4), 402-408.
[http://dx.doi.org/10.1006/meth.2001.1262] [PMID: 11846609]
[21]
Sun, S.; Lei, Y.; Li, Q.; Wu, Y.; Zhang, L.; Mu, P.P.; Ji, G.Q.; Tang, C.X.; Wang, Y.Q.; Gao, J.; Gao, J.; Li, L.; Zhuo, L.; Li, Y.Q.; Gao, D.S. Neuropilin-1 is a glial cell line-derived neurotrophic factor receptor in glioblastoma. Oncotarget, 2017, 8(43), 74019-74035.
[http://dx.doi.org/10.18632/oncotarget.18630] [PMID: 29088765]
[22]
Zheng, Y.G.; Wu, X.Q.; Su, J.; Jiang, P.; Xu, L.; Gao, J.; Cai, B.; Ji, M. Design and synthesis of a novel photoaffinity probe for labelling EGF receptor tyrosine kinases. J. Enzyme Inhib. Med. Chem., 2017, 32(1), 954-959.
[http://dx.doi.org/10.1080/14756366.2017.1344979] [PMID: 28718674]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy