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Robinetin Alleviates Metabolic Failure in Liver through Suppression of p300-CD38 Axis

  • Received : 2023.03.22
  • Accepted : 2023.10.10
  • Published : 2024.03.01

Abstract

Metabolic abnormalities in the liver are closely associated with diverse metabolic diseases such as non-alcoholic fatty liver disease, type 2 diabetes, and obesity. The aim of this study was to evaluate the ameliorating effect of robinetin (RBN) on the significant pathogenic features of metabolic failure in the liver and to identify the underlying molecular mechanism. RBN significantly decreased triglyceride (TG) accumulation by downregulating lipogenesis-related transcription factors in AML-12 murine hepatocyte cell line. In addition, mice fed with Western diet (WD) containing 0.025% or 0.05% RBN showed reduced liver mass and lipid droplet size, as well as improved plasma insulin levels and homeostatic model assessment of insulin resistance (HOMA-IR) values. CD38 was identified as a target of RBN using the BioAssay database, and its expression was increased in OPA-treated AML-12 cells and liver tissues of WD-fed mice. Furthermore, RBN elicited these effects through its anti-histone acetyltransferase (HAT) activity. Computational simulation revealed that RBN can dock into the HAT domain pocket of p300, a histone acetyltransferase, which leads to the abrogation of its catalytic activity. Additionally, knock-down of p300 using siRNA reduced CD38 expression. The chromatin immunoprecipitation (ChIP) assay showed that p300 occupancy on the promoter region of CD38 was significantly decreased, and H3K9 acetylation levels were diminished in lipid-accumulated AML-12 cells treated with RBN. RBN improves the pathogenic features of metabolic failure by suppressing the p300-CD38 axis through its anti-HAT activity, which suggests that RBN can be used as a new phytoceutical candidate for preventing or improving this condition.

Keywords

Acknowledgement

This work was supported by the Main Research Program (E-0210400 and E-0210601) of the Korea Food Research Institute (KFRI) and funded by the Ministry of Science, ICT & Future Planning. Part of this paper was presented as a poster at FEBS2023.

References

  1. Aagaard-Tillery, K. M., Grove, K., Bishop, J., Ke, X., Fu, Q., McKnight, R. and Lane, R. H. (2008) Developmental origins of disease and determinants of chromatin structure: maternal diet modifies the primate fetal epigenome. J. Mol. Endocrinol. 41, 91-102. https://doi.org/10.1677/JME-08-0025
  2. Barbosa, M. T., Soares, S. M., Novak, C. M., Sinclair, D., Levine, J. A., Aksoy, P. and Chini, E. N. (2007) The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet-induced obesity. FASEB J. 21, 3629-3639. https://doi.org/10.1096/fj.07-8290com
  3. Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., Shindyalov, I. N. and Bourne, P. E. (2000) The protein data bank. Nucleic Acids Res. 28, 235-242. https://doi.org/10.1093/nar/28.1.235
  4. Bowers, E. M., Yan, G., Mukherjee, C., Orry, A., Wang, L., Holbert, M. A., Crump, N. T., Hazzalin, C. A., Liszczak, G., Yuan, H., Larocca, C., Saldanha, S. A., Abagyan, R., Sun, Y., Meyers, D. J., Marmorstein, R., Mahadevan, L. C., Alani, R. M. and Cole, P. A. (2010) Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor. Chem. Biol. 17, 471-482. https://doi.org/10.1016/j.chembiol.2010.03.006
  5. Bricambert, J., Miranda, J., Benhamed, F., Girard, J., Postic, C. and Dentin, R. (2010) Salt-inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention of ChREBP-dependent hepatic steatosis in mice. J. Clin. Invest. 120, 4316-4331. https://doi.org/10.1172/JCI41624
  6. Camacho-Pereira, J., Tarrago, M. G., Chini, C. C. S., Nin, V., Escande, C., Warner, G. M., Puranik, A. S., Schoon, R. A., Reid, J. M., Galina, A. and Chini, E. N. (2016) CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab. 23, 1127-1139. https://doi.org/10.1016/j.cmet.2016.05.006
  7. Chaudhuri, S., Pahari, B., Sengupta, B. and Sengupta, P. K. (2010) Binding of the bioflavonoid robinetin with model membranes and hemoglobin: inhibition of lipid peroxidation and protein glycosylation. J. Photochem. Photobiol. B 98, 12-19. https://doi.org/10.1016/j.jphotobiol.2009.10.002
  8. Chen, C., Liu, Q., Liu, L., Hu, Y. Y. and Feng, Q. (2018) Potential biological effects of (-)-epigallocatechin-3-gallate on the treatment of nonalcoholic fatty liver disease. Mol. Nutr. Food Res. 62, 1700483.
  9. Chen, H., Lin, R. J., Xie, W., Wilpitz, D. and Evans, R. M. (1999) Regulation of hormone-induced histone hyperacetylation and gene activation via acetylation of an acetylase. Cell 98, 675-686. https://doi.org/10.1016/S0092-8674(00)80054-9
  10. Chiang, S. H., Harrington, W. W., Luo, G., Milliken, N. O., Ulrich, J. C., Chen, J., Rajpal, D. K., Qian, Y., Carpenter, T., Murray, R., Geske, R. S., Stimpson, S. A., Kramer, H. F., Haffner, C. D., Becherer, J. D., Preugschat, F. and Billin, A. N. (2015) Genetic ablation of CD38 Protects against western diet-induced exercise intolerance and metabolic Inflexibility. PLoS One 10, e0134927.
  11. Chung, M. Y., Song, J. H., Lee, J., Shin, E. J., Park, J. H., Lee, S. H., Hwang, J. T. and Choi, H. K. (2019) Tannic acid, a novel histone acetyltransferase inhibitor, prevents non-alcoholic fatty liver disease both in vivo and in vitro model. Mol. Metab. 19, 34-48. https://doi.org/10.1016/j.molmet.2018.11.001
  12. Escande, C., Nin, V., Price, N. L., Capellini, V., Gomes, A. P., Barbosa, M. T., O'Neil, L., White, T. A., Sinclair, D. A. and Chini, E. N. (2013) Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes 62, 1084-1093. https://doi.org/10.2337/db12-1139
  13. Eslam, M., Valenti, L. and Romeo, S. (2018) Genetics and epigenetics of NAFLD and NASH: clinical impact. J. Hepatol. 68, 268-279. https://doi.org/10.1016/j.jhep.2017.09.003
  14. Evans, R. M., Barish, G. D. and Wang, Y. X. (2004) PPARs and the complex journey to obesity. Nat. Med. 10, 355-361. https://doi.org/10.1038/nm1025
  15. Fesen, M. R., Pommier, Y., Leteurtre, F., Hiroguchi, S., Yung, J. and Kohn, K. W. (1994) Inhibition of HIV-1 integrase by flavones, caffeic acid phenethyl ester (CAPE) and related compounds. Biochem. Pharmacol. 48, 595-608. https://doi.org/10.1016/0006-2952(94)90291-7
  16. Fujii, H., Kawada, N. and Japan Study Group Of Nafld, J.-N. (2020) The role of insulin resistance and diabetes in nonalcoholic fatty liver disease. Int. J. Mol. Sci. 21, 3863.
  17. Funaro, A. and Malavasi, F. (1999) Human CD38, a surface receptor, an enzyme, an adhesion molecule and not a simple marker. J. Biol. Regul. Homeost. Agents 13, 54-61.
  18. Gorniak, I., Bartoszewski, R. and Kroliczewski, J. (2019) Comprehensive review of antimicrobial activities of plant flavonoids. Phytochem. Rev. 18, 241-272. https://doi.org/10.1007/s11101-018-9591-z
  19. Gruben, N., Shiri-Sverdlov, R., Koonen, D. P. and Hofker, M. H. (2014) Nonalcoholic fatty liver disease: a main driver of insulin resistance or a dangerous liaison? Biochim. Biophys. Acta 1842, 2329-2343. https://doi.org/10.1016/j.bbadis.2014.08.004
  20. Hennig, A. K., Peng, G. H. and Chen, S. (2013) Transcription coactivators p300 and CBP are necessary for photoreceptor-specific chromatin organization and gene expression. PLoS One 8, e69721.
  21. Horenstein, A. L., Faini, A. C. and Malavasi, F. (2021) CD38 in the age of COVID-19: a medical perspective. Physiol. Rev. 101, 1457-1486. https://doi.org/10.1152/physrev.00046.2020
  22. Kalaany, N. Y., Gauthier, K. C., Zavacki, A. M., Mammen, P. P., Kitazume, T., Peterson, J. A., Horton, J. D., Garry, D. J., Bianco, A. C. and Mangelsdorf, D. J. (2005) LXRs regulate the balance between fat storage and oxidation. Cell Metab. 1, 231-244. https://doi.org/10.1016/j.cmet.2005.03.001
  23. Kessoku, T., Imajo, K., Honda, Y., Kato, T., Ogawa, Y., Tomeno, W., Kato, S., Mawatari, H., Fujita, K., Yoneda, M., Nagashima, Y., Saito, S., Wada, K. and Nakajima, A. (2016) Resveratrol ameliorates fibrosis and inflammation in a mouse model of nonalcoholic steatohepatitis. Sci. Rep. 6, 22251.
  24. Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., Li, Q., Shoemaker, B. A., Thiessen, P. A., Yu, B., Zaslavsky, L., Zhang, J. and Bolton, E. E. (2019) PubChem 2019 update: improved access to chemical data. Nucleic Acids Res. 47, D1102-D1109. https://doi.org/10.1093/nar/gky1033
  25. Kim, S. Y., Cho, B. H. and Kim, U. H. (2010) CD38-mediated Ca2+ signaling contributes to angiotensin II-induced activation of hepatic stellate cells: attenuation of hepatic fibrosis by CD38 ablation. J. Biol. Chem. 285, 576-582. https://doi.org/10.1074/jbc.M109.076216
  26. Ling, C. and Groop, L. (2009) Epigenetics: a molecular link between environmental factors and type 2 diabetes. Diabetes 58, 2718-2725. https://doi.org/10.2337/db09-1003
  27. Liu, X., Wang, L., Zhao, K., Thompson, P. R., Hwang, Y., Marmorstein, R. and Cole, P. A. (2008) The structural basis of protein acetylation by the p300/CBP transcriptional coactivator. Nature 451, 846-850. https://doi.org/10.1038/nature06546
  28. Loomba, R., Abraham, M., Unalp, A., Wilson, L., Lavine, J., Doo, E. and Bass, N. M.; Nonalcoholic Steatohepatitis Clinical Research Network. (2012) Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology 56, 943-951. https://doi.org/10.1002/hep.25772
  29. Lu, L., Wang, J., Yang, Q., Xie, X. and Huang, Y. (2021) The role of CD38 in HIV infection. AIDS Res. Ther. 18, 11.
  30. Maksimoska, J., Segura-Pena, D., Cole, P. A. and Marmorstein, R. (2014) Structure of the p300 histone acetyltransferase bound to acetyl-coenzyme A and its analogues. Biochemistry 53, 3415-3422. https://doi.org/10.1021/bi500380f
  31. Mikula, M., Majewska, A., Ledwon, J. K., Dzwonek, A. and Ostrowski, J. (2014) Obesity increases histone H3 lysine 9 and 18 acetylation at Tnfa and Ccl2 genes in mouse liver. Int. J. Mol. Med. 34, 1647-1654. https://doi.org/10.3892/ijmm.2014.1958
  32. Moon, Y. A. (2017) The SCAP/SREBP pathway: a mediator of hepatic steatosis. Endocrinol. Metab. (Seoul) 32, 6-10. https://doi.org/10.3803/EnM.2017.32.1.6
  33. Morandi, F., Horenstein, A. L., Costa, F., Giuliani, N., Pistoia, V. and Malavasi, F. (2018) CD38: a target for immunotherapeutic approaches in multiple myeloma. Front. Immunol. 9, 2722.
  34. Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S. and Olson, A. J. (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J. Comput. Chem. 30, 2785-2791. https://doi.org/10.1002/jcc.21256
  35. Piedra-Quintero, Z. L., Wilson, Z., Nava, P. and Guerau-de-Arellano, M. (2020) CD38: an immunomodulatory molecule in inflammation and autoimmunity. Front. Immunol. 11, 597959.
  36. Rahman, S. M., Schroeder-Gloeckler, J. M., Janssen, R. C., Jiang, H., Qadri, I., Maclean, K. N. and Friedman, J. E. (2007) CCAAT/enhancing binding protein beta deletion in mice attenuates inflammation, endoplasmic reticulum stress, and lipid accumulation in diet-induced nonalcoholic steatohepatitis. Hepatology 45, 1108-1117. https://doi.org/10.1002/hep.21614
  37. Sarwar, R., Pierce, N. and Koppe, S. (2018) Obesity and nonalcoholic fatty liver disease: current perspectives. Diabetes Metab. Syndr. Obes. 11, 533-542. https://doi.org/10.2147/DMSO.S146339
  38. Thompson, P. R., Wang, D., Wang, L., Fulco, M., Pediconi, N., Zhang, D., An, W., Ge, Q., Roeder, R. G., Wong, J., Levrero, M., Sartorelli, V., Cotter, R. J. and Cole, P. A. (2004) Regulation of the p300 HAT domain via a novel activation loop. Nat. Struct. Mol. Biol. 11, 308-315. https://doi.org/10.1038/nsmb740
  39. Tolsma, T. O. and Hansen, J. C. (2019) Post-translational modifications and chromatin dynamics. Essays Biochem. 63, 89-96. https://doi.org/10.1042/EBC20180067
  40. Trott, O. and Olson, A. J. (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31, 455-461. https://doi.org/10.1002/jcc.21334
  41. Verdone, L., Agricola, E., Caserta, M. and Di Mauro, E. (2006) Histone acetylation in gene regulation. Brief. Funct. Genomic. Proteomic. 5, 209-221. https://doi.org/10.1093/bfgp/ell028
  42. Wang, L. F., Miao, L. J., Wang, X. N., Huang, C. C., Qian, Y. S., Huang, X., Wang, X. L., Jin, W. Z., Ji, G. J., Fu, M., Deng, K. Y. and Xin, H. B. (2018) CD38 deficiency suppresses adipogenesis and lipogenesis in adipose tissues through activating Sirt1/PPARgamma signaling pathway. J. Cell. Mol. Med. 22, 101-110. https://doi.org/10.1111/jcmm.13297
  43. Wang, Y., Bryant, S. H., Cheng, T., Wang, J., Gindulyte, A., Shoemaker, B. A., Thiessen, P. A., He, S. and Zhang, J. (2017) PubChem BioAssay: 2017 update. Nucleic Acids Res. 45, D955-D963. https://doi.org/10.1093/nar/gkw1118
  44. Williams, C. D., Stengel, J., Asike, M. I., Torres, D. M., Shaw, J., Contreras, M., Landt, C. L. and Harrison, S. A. (2011) Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 140, 124-131. https://doi.org/10.1053/j.gastro.2010.09.038
  45. Yan, X., Qi, M., Li, P., Zhan, Y. and Shao, H. (2017) Apigenin in cancer therapy: anti-cancer effects and mechanisms of action. Cell Biosci. 7, 50.
  46. Zhao, S., Xu, W., Jiang, W., Yu, W., Lin, Y., Zhang, T., Yao, J., Zhou, L., Zeng, Y., Li, H., Li, Y., Shi, J., An, W., Hancock, S. M., He, F., Qin, L., Chin, J., Yang, P., Chen, X., Lei, Q., Xiong, Y. and Guan, K. L. (2010) Regulation of cellular metabolism by protein lysine acetylation. Science 327, 1000-1004. https://doi.org/10.1126/science.1179689
  47. Zhu, X. Y., Huang, C. S., Li, Q., Chang, R. M., Song, Z. B., Zou, W. Y. and Guo, Q. L. (2012) p300 exerts an epigenetic role in chronic neuropathic pain through its acetyltransferase activity in rats following chronic constriction injury (CCI). Mol. Pain 8, 84.