Purple sweet potato color protects against hepatocyte apoptosis through Sirt1 activation in high-fat-diet-treated mice

  • Weitong Su
  • Cheng Zhang
  • Feng Chen
  • Junwen Sui
  • Jiaqi Lu
  • Qingqing Wang
  • Qun Shan
  • Guihong Zheng
  • Jun Lu
  • Chunhui Sun
  • Shaohua Fan
  • Dongmei Wu
  • Zifeng Zhang
  • Yuanlin Zheng
Keywords: purple sweet potato color; hepatic apoptosis; Sirt1; P53; Akt; high-fat diet

Abstract

Background: Recent evidence indicates that the inhibition of hepatocyte apoptosis is possible to develop a potential therapeutic strategy for nonalcoholic fatty liver disease (NAFLD). Our previous work suggested that purple sweet potato color (PSPC), a class of naturally occurring anthocyanins, effectively improved many features of high-fat diet (HFD)-induced NAFLD. However, whether PSPC ameliorates HFD-induced hepatocyte apoptosis has never been investigated.

Objective: Here we investigated the effects of PSPC on HFD-induced hepatic apoptosis and the mechanisms underlying these effects.

Design: Mice were divided into four groups: Control group, HFD group, HFD + PSPC group and PSPC group. PSPC was administered by daily oral gavage at doses of 700 mg/kg/day for 20 weeks. EX-527 (a SirT1-selective inhibitor) and Sirt1 siRNA were used to demonstrate the Sirt1 dependence of PSPC-mediated effects on apoptotic and survival signaling pathways in vivo and in vitro.

Results: Our results showed that PSPC reduced body weights, hepatic triglyceride contents, histopathological lesions and serum ALT levels in a mouse model of NAFLD induced by HFD. Furthermore, PSPC attenuated HFD-induced hepatocyte apoptosis ratio from 7.27 ± 0.92% to 1.79 ± 0.27% in mouse livers, which is insignificant compared with that of controls. Moreover, PSPC activated Sirt1 by boosting NAD+ level in HFD-treated mouse livers. Furthermore, PSPC promoted Sirt1-dependent suppression of P53-mediated apoptotic signaling and activation of Akt survival signaling pathway in HFD-treated mouse livers, which was confirmed by EX527 treatment. Moreover, Sirt1 knockdown abolished these ameliorative effects of PSPC on apoptosis and P53 acetylation and protein expression in PA-treated L02 cells. Ultimately, PSPC reduced Caspase-3 activation and Bax level, and elevated the Bcl-2 level in HFD-treated mouse livers.

Conclusion: PSPC protected against HFD-induced hepatic apoptosis by promoting Sirt1- dependent inhibition of p53-apoptotic pathway and facilitation of Akt survival pathway. This study indicates that PSPC is a candidate for nutritional intervention of NAFLD.

Downloads

Download data is not yet available.

References


  1. Cusi K, Sanyal A, Zhang S, Hartman ML, Bue-Valleskey JM, Hoogwerf BJ, et al. Non-alcoholic fatty liver disease (NAFLD) prevalence and its metabolic associations in patients with type 1 diabetes and type 2 diabetes. Diabetes Obes Metab 2017; 19(11): 1630–34. doi: 10.1111/dom.12973

  2. Mantovani A, Byrne CD, Bonora E, Targher G. Nonalcoholic fatty liver disease and risk of incident type 2 diabetes: a meta-analysis. Diabetes Care 2018; 41(2): 372–82. doi: 10.2337/dc17-1902

  3. Stokes CS, Lammert F, Krawczyk M. Short-term dietary interventions for the management of nonalcoholic fatty liver. Curr Med Chem 2019; 26(19): 3483–96. doi: 10.2174/0929867324666170508144409

  4. Kanda T, Matsuoka S, Yamazaki M, Shibata T, Nirei K, Takahashi H, et al. Apoptosis and non-alcoholic fatty liver diseases. World J Gastroenterol 2018; 24(25): 2661–72. doi: 10.3748/wjg.v24.i25.2661

  5. Ezquerro S, Mocha F, Frühbeck G, Guzmán-Ruiz R, Valentí V, Mugueta C, et al. Ghrelin reduces TNF-α-induced human hepatocyte apoptosis, autophagy, and pyroptosis: role in obesity-associated NAFLD. J Clin Endocrinol Metab 2019; 104(1): 21–37. doi: 10.1210/jc.2018-01171

  6. Qiao JT, Cui C, Qing L, Wang LS, He TY, Yan F, et al. Activation of the STING-IRF3 pathway promotes hepatocyte inflammation, apoptosis and induces metabolic disorders in nonalcoholic fatty liver disease. Metabolism 2018; 81: 13–24. doi: 10.1016/j.metabol.2017.09.010

  7. Shan W, Gao L, Zeng W, Hu Y, Wang G, Li M, et al. Activation of the SIRT1/p66shc antiapoptosis pathway via carnosic acid-induced inhibition of miR-34a protects rats against nonalcoholic fatty liver disease. Cell Death Dis 2015; 6: e1833. doi: 10.1038/cddis.2015.196

  8. Mijeong K, Minji W, Jeong SN, Eunok C, Yeong OS. Sesame oil lignans inhibit hepatic endoplasmic reticulum stress and apoptosis in high-fat diet-fed mice. J Funct Foods 2017; 37: 658–65. doi: 10.1016/j.jff.2017.08.036

  9. Salomone F, Barbagallo I, Godos J, Lembo V, Currenti W, Cinà D, et al. Silibinin restores NAD+ levels and induces the SIRT1/AMPK pathway in non-alcoholic fatty liver. Nutrients 2017; 9(10): pii: E1086. doi: 10.3390/nu9101086

  10. Rajman L, Chwalek K, Sinclair DA. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metab 2018; 27(3): 529–47. doi: 10.1016/j.cmet.2018.02.011

  11. Wang G, Yao J, Li Z, Zu G, Feng D, Shan W, et al. miR-34a-5p inhibition alleviates intestinal ischemia/reperfusion-induced reactive oxygen species accumulation and apoptosis via activation of SIRT1 signaling. Antioxid Redox Signal 2016; 24(17): 961–73. doi: 10.1089/ars.2015.6492

  12. Xu RY, Xu XW, Deng YZ, Ma ZX, Li XR, Zhao L, et al. Resveratrol attenuates myocardial hypoxia/reoxygenation-induced cell apoptosis through DJ-1-mediated SIRT1-p53 pathway. Biochem Biophys Res Commun 2019; 514(2): 401–6. doi: 10.1016/j.bbrc.2019.04.165

  13. Castro RE, Ferreira DM, Afonso MB, Borralho PM, Machado MV, Cortez-Pinto H, et al. miR-34a/SIRT1/p53 is suppressed by ursodeoxycholic acid in the rat liver and activated by disease severity in human non-alcoholic fatty liver disease. J Hepatol 2013; 58(1): 119–25. doi: 10.1016/j.jhep.2012.08.008

  14. Esatbeyoglu T, Rodríguez-Werner M, Schlösser A, Winterhalter P, Rimbach G. Fractionation, enzyme inhibitory and cellular antioxidant activity of bioactives from purple sweet potato (Ipomoea batatas). Food Chem 2017; 221: 447–56. doi: 10.1016/j.foodchem.2016.10.077

  15. Zhang ZF, Fan SH, Zheng YL, Lu J, Wu DM, Shan Q, et al. Purple sweet potato color attenuates oxidative stress and inflammatory response induced by d-galactose in mouse liver. Food Chem Toxicol 2009; 47(2): 496–501. doi: 10.1016/j.fct.2008.12.005

  16. Li WL, Yu HY, Zhang XJ, Ke M, Hong T. Purple sweet potato anthocyanin exerts antitumor effect in bladder cancer. Oncol Rep 2018; 40(1): 73–82. doi: 10.3892/or.2018.6421

  17. Wang X, Zhang ZF, Zheng GH, Wang AM, Sun CH, Qin SP, et al. Attenuation of hepatic steatosis by purple sweet potato colour is associated with blocking Src/ERK/C/EBPβ signalling in high-fat-diet-treated mice. Appl Physiol Nutr Metab 2017; 42(10): 1082–91. doi: 10.1139/apnm-2016-0635

  18. Wang X, Zhang ZF, Zheng GH, Wang AM, Sun CH, Qin SP, et al. The inhibitory effects of purple sweet potato color on hepatic inflammation is associated with restoration of NAD+ levels and attenuation of NLRP3 inflammasome activation in high-fat-diet-treated mice. Molecules 2017; 22(8): pii: E1315. doi: 10.3390/molecules22081315

  19. Zhang ZF, Lu J, Zheng YL, Wu DM, Hu B, Shan Q, et al. Purple sweet potato color attenuates hepatic insulin resistance via blocking oxidative stress and endoplasmic reticulum stress in high-fat-diet-treated mice. J Nutr Biochem 2013; 24(6): 1008–18. doi: 10.1016/j.jnutbio.2012.07.009

  20. Zhang M, Pan LJ, Jiang ST, Mo YW. Protective effects of anthocyanins from purple sweet potato on acute carbon tetrachloride-induced oxidative hepatotoxicity fibrosis in mice. Food Agricultural Immunol 2016; 27(2): 157–70. doi: 10.1080/09540105.2015.1079589

  21. Zhang ZF, Lu J, Zheng YL, Hu B, Fan SH, Wu DM, et al. Purple sweet potato color protects mouse liver against d-galactose-induced apoptosis via inhibiting caspase-3 activation and enhancing PI3K/Akt pathway. Food Chem Toxicol 2010; 48(8–9): 2500–7. doi: 10.1016/j.fct.2010.06.023

  22. Lu J, Wu DM, Zheng YL, Hu B, Cheng W, Zhang ZF. Purple sweet potato color attenuates domoic acid-induced cognitive deficits by promoting estrogen receptor-α-mediated mitochondrial biogenesis signaling in mice. Free Radic Biol Med 2012; 52(3): 646–59. doi: 10.1016/j.freeradbiomed.2011.11.016

  23. Zhang ZF, Fan SH, Zheng YL, Lu J, Wu DM, Shan Q, et al. Troxerutin improves hepatic lipid homeostasis by restoring NAD(+)-depletion-mediated dysfunction of lipin 1 signaling in high-fat diet-treated mice. Biochem Pharmacol 2014; 91(1): 74–86. doi: 10.1016/j.bcp.2014.07.002

  24. Folch J, Lees M, Sloane Stanley GH. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 1957; 226(1): 497–509. PMID: 13428781. Available from: http://www.jbc.org/content/226/1/497.citation.full.Html#ref-list-1

  25. Sun C, Diao Q, Lu J, Zhang Z, Wu D, Wang X, et al. Purple sweet potato color attenuated NLRP3 inflammasome by inducing autophagy to delay endothelial senescence. J Cell Physiol 2019; 234(5): 5926–39. doi: 10.1002/jcp.28003

  26. Chen Q, Wang T, Li J, Wang S, Qiu F, Yu H, et al. Effects of natural products on fructose-induced nonalcoholic fatty liver disease (NAFLD). Nutrients 2017; 9(2): pii: E96. doi: 10.3390/nu9020096

  27. Bagherniya M, Nobili V, Blesso CN, Sahebkar A. Medicinal plants and bioactive natural compounds in the treatment of non-alcoholic fatty liver disease: a clinical review. Pharmacol Res 2018; 130: 213–40. doi: 10.1016/j.phrs.2017.12.020

  28. Feng X, Yu W, Li X, Zhou F, Zhang W, Shen Q, et al. Apigenin, a modulator of PPARgamma, attenuates HFD-induced NAFLD by regulating hepatocyte lipid metabolism and oxidative stress via Nrf2 activation. Biochem Pharmacol 2017; 136: 136–49. doi: 10.1016/j.bcp.2017.04.014

  29. Takahara I, Akazawa Y, Tabuchi M, Matsuda K, Miyaaki H, Kido Y, et al. Toyocamycin attenuates free fatty acid-induced hepatic steatosis and apoptosis in cultured hepatocytes and ameliorates nonalcoholic fatty liver disease in mice. PLoS One 2017; 12(3): e0170591. doi: 10.1371/journal.pone.0170591

  30. Sommerfeld A, Reinehr R, Häussinger D. Free fatty acids shift insulin-induced hepatocyte proliferation towards CD95-dependent apoptosis. J Biol Chem 2015; 290(7): 4398–409. doi: 10.1074/jbc.M114.617035

  31. Sánchez-Rodríguez C, Cuadrado E, Riestra-Ayora J, Sanz-Fernández R. Polyphenols protect against age-associated apoptosis in female rat cochleae. Biogerontology 2018; 19(2): 159–69. doi: 10.1007/s10522-018-9747-7

  32. Guo S, Yao Q, Ke Z, Chen H, Wu J, Liu C. Resveratrol attenuates high glucose-induced oxidative stress and cardiomyocyte apoptosis through AMPK. Mol Cell Endocrinol 2015; 412: 85–94. doi: 10.1016/j.mce.2015.05.034

  33. Sharma S, Rana S, Patial V, Gupta M, Bhushan S, Padwad YS. Antioxidant and hepatoprotective effect of polyphenols from apple pomace extract via apoptosis inhibition and Nrf2 activation in mice. Hum Exp Toxicol 2016; 35(12): 1264–75. doi: 10.1177/0960327115627689

  34. Duan WX, He MD, Mao L, Qian FH, Li YM, Pi HF, et al. NiO nanoparticles induce apoptosis through repressing SIRT1 in human bronchial epithelial cells. Toxicol Appl Pharmacol 2015; 286(2): 80–91. doi: 10.1016/j.taap.2015.03.024

  35. Ren T, Zhu L, Shen Y, Mou Q, Lin T, Feng H. Protection of hepatocyte mitochondrial function by blueberry juice and probiotics via SIRT1 regulation in non-alcoholic fatty liver disease. Food Funct 2019; 10(3): 1540–51. doi: 10.1039/c8fo02298d

  36. Derdak Z1, Villegas KA, Harb R, Wu AM, Sousa A, Wands JR. Inhibition of p53 attenuates steatosis and liver injury in a mouse model of non-alcoholic fatty liver disease. J Hepatol 2013; 58(4): 785–91. doi: 10.1016/j.jhep.2012.11.042

  37. Liu K, Lou J, Wen T, Yin J, Xu B, Ding W, et al. Depending on the stage of hepatosteatosis, p53 causes apoptosis primarily through either DRAM-induced autophagy or BAX. Liver Int 2013; 33(10): 1566–74. doi: 10.1111/liv.12238

  38. Nakamura K, Zhang M, Kageyama S, Ke B, Fujii T, Sosa RA, et al. Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia-reperfusion injury. J Hepatol 2017; 67(6): 1232–42. doi: 10.1016/j.jhep.2017.08.010

  39. Caromile LA, Dortche K, Rahman MM, Grant CL, Stoddard C, Ferrer FA, et al. PSMA redirects cell survival signaling from the MAPK to the PI3K-AKT pathways to promote the progression of prostate cancer. Sci Signal 2017; 10(470): pii: eaag3326. doi: 10.1126/scisignal.aag3326

  40. Kapodistria K, Tsilibary EP, Kotsopoulou E, Moustardas P, Kitsiou P. Liraglutide, a human glucagon-like peptide-1 analogue, stimulates AKT-dependent survival signalling and inhibits pancreatic beta-cell apoptosis. J Cell Mol Med 2018; 22(6): 2970–80. doi: 10.1111/jcmm.13259

  41. Xu H, Li J, Wang Z, Feng M, Shen Y, Cao S, et al. Methylene blue attenuates neuroinflammation after subarachnoid hemorrhage in rats through the Akt/GSK-3beta/MEF2D signaling pathway. Brain Behav Immun 2017; 65: 125–39. doi: 10.1016/j.bbi.2017.04.020

  42. Wang W, Yi M, Chen S, Li J, Zhang H, Xiong W, et al. NOR1 suppresses cancer stem-like cells properties of tumor cells via the inhibition of the AKT-GSK-3beta-Wnt/beta-catenin-ALDH1A1 signal circuit. J Cell Physiol 2017; 232(10): 2829–40. doi: 10.1002/jcp.25706

  43. Li Q, Peng Y, Fan L, Xu H, He P, Cao S, et al. Phosphodiesterase-4 inhibition confers a neuroprotective efficacy against early brain injury following experimental subarachnoid hemorrhage in rats by attenuating neuronal apoptosis through the SIRT1/Akt pathway. Biomed Pharmacother 2018; 99: 947–55. doi: 10.1016/j.biopha.2018.01.093

  44. Renaud J, Bournival J, Zottig X, Martinoli MG. Resveratrol protects DAergic PC12 cells from high glucose-induced oxidative stress and apoptosis: effect on p53 and GRP75 localization. Neurotox Res 2014; 25(1): 110–23. doi: 10.1007/s12640-013-9439-7

  45. Ding ML, Ma H, Man YG, Lv HY. Protective effects of a green tea polyphenol, epigallocatechin-3-gallate, against sevoflurane-induced neuronal apoptosis involve regulation of CREB/BDNF/ TrkB and PI3K/Akt/mTOR signalling pathways in neonatal mice. Can J Physiol Pharmacol 2017; 95(12): 1396–405. doi: 10.1139/cjpp-2016-0333

  46. Cantó C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, et al. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab 2012; 15(6): 838–47. doi: 10.1016/j.cmet.2012.04.022

  47. Stromsdorfer KL, Yamaguchi S, Yoon MJ, Moseley AC, Franczyk MP, Kelly SC, et al. NAMPT-mediated NAD(+) biosynthesis in adipocytes regulates adipose tissue function and multi-organ insulin sensitivity in mice. Cell Rep 2016; 16(7): 1851–60. doi: 10.1016/j.celrep.2016.07.027.

  48. Tullius SG, Biefer HR, Li S, Trachtenberg AJ, Edtinger K, Quante M, et al. NAD+ protects against EAE by regulating CD4+ T-cell differentiation. Nat Commun 2014; 5: 5101. doi: 10.1038/ncomms6101

  49. Gerdts J, Brace EJ, Sasaki Y, DiAntonio A, Milbrandt J. SARM1 activation triggers axon degeneration locally via NAD(+) destruction. Science 2015; 348(6233): 453–7. doi: 10.1126/science.1258366

  50. Escande C, Nin V, Price NL, Capellini V, Gomes AP, Barbosa MT, et al. Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes 2013; 62(4): 1084–93. doi: 10.2337/db12-1139

  51. Han X, Tai H, Wang X, Wang Z, Zhou J, Wei X, et al. AMPK activation protects cells from oxidative stress-induced senescence via autophagic flux restoration and intracellular NAD(+) elevation. Aging Cell 2016; 15(3): 416–27. doi: 10.1111/acel.12446

  52. Jang KH, Jang T, Son E, Choi S, Kim E. Kinase-independent role of nuclear RIPK1 in regulating parthanatos through physical interaction with PARP1 upon oxidative stress. Biochim Biophys Acta Mol Cell Res 2018; 1865(1): 132–41. doi: 10.1016/j.bbamcr.2017.10.004

Published
2020-02-04
How to Cite
1.
Su W, Zhang C, Chen F, Sui J, Lu J, Wang Q, Shan Q, Zheng G, Lu J, Sun C, Fan S, Wu D, Zhang Z, Zheng Y. Purple sweet potato color protects against hepatocyte apoptosis through Sirt1 activation in high-fat-diet-treated mice. fnr [Internet]. 2020Feb.4 [cited 2020May27];64. Available from: https://foodandnutritionresearch.net/index.php/fnr/article/view/1509
Section
Original Articles