Epigallocatechin gallate suppresses hepatic cholesterol synthesis by targeting SREBP-2 through SIRT1/FOXO1 signaling pathway

  • Yongnan Li
  • Shuodong Wu


This study aims to explore the effect of epigallocatechin gallate (EGCG) on blood lipids, liver lipids, and cholesterol synthesis in hyperlipidemic rats. SREBP-2 transgenic rats were used to investigate the transcriptional level of SREBP-2 regulated by SIRT-1/FOXO1 and the molecular mechanism of rate-limiting enzyme HMGCR that affects cholesterol synthesis. Rat models of hyperlipidemia were established and administered EGCG. Cholesterol synthesis was observed. Enzyme linked immunosorbent assay was used to determine serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), free fatty acid (FFA), superoxide dismutase (SOD), malondialdehyde (MDA), and T-AOC contents. Hematoxylin-eosin staining and oil red O staining were utilized to observe the histological changes in the liver. Biochemical method was applied to measure serum ALT and AST changes. Western blot assay and qRT-PCR were employed to detect the changes in SIRT1/FOXO1 pathway-related proteins, cholesterol synthesis-related genes, and SREBP-2. EGCG 50 mg/kg could obviously decrease the liver weight and liver coefficient, reduce serum TG, TC, LDL-C, and FFA levels (P < 0.05), and increase serum HDL-C levels in hyperlipidemic rats. EGCG could diminish hyperlipidemia-induced liver injury and reduce serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Oil red O staining results demonstrated that the number of red lipid droplets in hepatocytes reduced to varying degrees, especially high-dose EGCG. EGCG remarkably diminished MDA content in the liver with hypercholesterolemia and increased T-AOC and SOD activity. In the model group, SIRT1 expression increased, and FOXO1 expression decreased. EGCG activated SIRT1 and increased FOXO1 expression, whose expression trend was consistent with the fenofibrate group. HMGCR, FDPS, SS, and ABCA1 expression increased, and ACAT2 expression noticeably reduced in SREBP-2+/+ transgenic rats. EGCG could reverse the expression trend of each gene. Simultaneously, EGCG increased FOXO1 expression, and decrease SREBP-2 expression; however, no significant changes in these expression were found in SREBP-2−/− rats. EGCG can alleviate liver injury and oxidative stress in hyperlipidemic rats. EGCG can activate SIRT1, activate FOXO1 protein, regulate SREBP-2 protein, and inhibit hepatic cholesterol synthesis.


SREBP-2 transgenic rats SREBP-2/SIRT1/FOXO1 signaling pathway Cholesterol synthesis 



This work was supported in part by Grants from National Natural Science Foundation of China (No. 81200318).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interest.


  1. 1.
    Sun Z, Miller RA, Patel RT, Chen J, Dhir R, Wang H, Zhang D, Graham MJ, Unterman TG, Shulman GI, Sztalryd C, Bennett MJ, Ahima RS, Birnbaum MJ, Lazar MA (2012) Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat Med 18(6):934–942. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M (2016) Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64(1):73–84. CrossRefPubMedGoogle Scholar
  3. 3.
    Zafar A, Al-Khamis FA, Al-Bakr AI, Alsulaiman AA, Msmar AH (2016) Risk factors and subtypes of acute ischemic stroke. A study at King Fahd Hospital of the University. Neurosciences 21(3):246–251. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Nelson RH (2013) Hyperlipidemia as a risk factor for cardiovascular disease. Primary Care 40(1):195–211. CrossRefPubMedGoogle Scholar
  5. 5.
    Yang EJ, Lee J, Lee SY, Kim EK, Moon YM, Jung YO, Park SH, Cho ML (2014) EGCG attenuates autoimmune arthritis by inhibition of STAT3 and HIF-1alpha with Th17/Treg control. PLoS ONE 9(2):e86062. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Tran PL, Kim SA, Choi HS, Yoon JH, Ahn SG (2010) Epigallocatechin-3-gallate suppresses the expression of HSP70 and HSP90 and exhibits anti-tumor activity in vitro and in vivo. BMC Cancer 10:276. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Singh BN, Shankar S, Srivastava RK (2011) Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications. Biochem Pharmacol 82(12):1807–1821. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Avadhani KS, Manikkath J, Tiwari M, Chandrasekhar M, Godavarthi A, Vidya SM, Hariharapura RC, Kalthur G, Udupa N, Mutalik S (2017) Skin delivery of epigallocatechin-3-gallate (EGCG) and hyaluronic acid loaded nano-transfersomes for antioxidant and anti-aging effects in UV radiation induced skin damage. Drug Deliv 24(1):61–74. CrossRefPubMedGoogle Scholar
  9. 9.
    Yamabe N, Yokozawa T, Oya T, Kim M (2006) Therapeutic potential of (-)-epigallocatechin 3-O-gallate on renal damage in diabetic nephropathy model rats. J Pharmacol Exp Ther 319(1):228–236. CrossRefPubMedGoogle Scholar
  10. 10.
    Kaviarasan S, Sundarapandiyan R, Anuradha CV (2008) Epigallocatechin gallate, a green tea phytochemical, attenuates alcohol-induced hepatic protein and lipid damage. Toxicol Mech Methods 18(8):645–652. CrossRefPubMedGoogle Scholar
  11. 11.
    Itoh T, Tabuchi M, Mizuguchi N, Imano M, Tsubaki M, Nishida S, Hashimoto S, Matsuo K, Nakayama T, Ito A, Munakata H, Satou T (2013) Neuroprotective effect of (-)-epigallocatechin-3-gallate in rats when administered pre- or post-traumatic brain injury. J Neural Transm 120(5):767–783. CrossRefPubMedGoogle Scholar
  12. 12.
    Funamoto M, Masumoto H, Takaori K, Taki T, Setozaki S, Yamazaki K, Minakata K, Ikeda T, Hyon SH, Sakata R (2016) Green tea polyphenol prevents diabetic rats from acute kidney injury after cardiopulmonary bypass. Ann Thorac Surg 101(4):1507–1513. CrossRefPubMedGoogle Scholar
  13. 13.
    Miltonprabu S, Thangapandiyan S (2015) Epigallocatechin gallate potentially attenuates fluoride induced oxidative stress mediated cardiotoxicity and dyslipidemia in rats. J Trace Elem Med Biol 29:321–335. CrossRefPubMedGoogle Scholar
  14. 14.
    Bose M, Lambert JD, Ju J, Reuhl KR, Shapses SA, Yang CS (2008) The major green tea polyphenol, (-)-epigallocatechin-3-gallate, inhibits obesity, metabolic syndrome, and fatty liver disease in high-fat-fed mice. J Nutr 138(9):1677–1683CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Haskins JW, Zhang S, Means RE, Kelleher JK, Cline GW, Canfran-Duque A, Suarez Y, Stern DF (2015) Neuregulin-activated ERBB4 induces the SREBP-2 cholesterol biosynthetic pathway and increases low-density lipoprotein uptake. Sci Signal 8(401):ra111. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Li Y, Song Y, Zhao M, Guo Y, Yu C, Chen W, Shao S, Xu C, Zhou X, Zhao L, Zhang Z, Bo T, Xia Y, Proud CG, Wang X, Wang L, Zhao J, Gao L (2017) A novel role for CRTC2 in hepatic cholesterol synthesis through SREBP-2. Hepatology 66(2):481–497. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kuhn DJ, Burns AC, Kazi A, Dou QP (2004) Direct inhibition of the ubiquitin-proteasome pathway by ester bond-containing green tea polyphenols is associated with increased expression of sterol regulatory element-binding protein 2 and LDL receptor. Biochim et Biophys Acta 1682(1–3):1–10. Google Scholar
  18. 18.
    Klotz LO, Sanchez-Ramos C, Prieto-Arroyo I, Urbanek P, Steinbrenner H, Monsalve M (2015) Redox regulation of FoxO transcription factors. Redox Biol 6:51–72. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Oh KJ, Han HS, Kim MJ, Koo SH (2013) CREB and FoxO1: two transcription factors for the regulation of hepatic gluconeogenesis. BMB Rep 46(12):567–574CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Wu Y, Liu X, Zhou Q, Huang C, Meng X, Xu F, Li J (2015) Silent information regulator 1 (SIRT1) ameliorates liver fibrosis via promoting activated stellate cell apoptosis and reversion. Toxicol Appl Pharmacol 289(2):163–176. CrossRefPubMedGoogle Scholar
  21. 21.
    Ren PL, Fan XJ, Yang XL, Liu MJ, Liu J, Huang JJ (2014) SIRT1 promote GTM cell DSBs repair and resist cellular senescence. J Sichuan Univ Med Sci Ed 45(4):572–577Google Scholar
  22. 22.
    Guo X, Williams JG, Schug TT, Li X (2010) DYRK1A and DYRK3 promote cell survival through phosphorylation and activation of SIRT1. J Biol Chem 285(17):13223–13232. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Li K, Zhang J, Yu J, Liu B, Guo Y, Deng J, Chen S, Wang C, Guo F (2015) MicroRNA-214 suppresses gluconeogenesis by targeting activating transcriptional factor 4. J Biol Chem 290(13):8185–8195. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Takahashi M, Ishibashi S (2013) Acquired hypertriglyceridemia. Nihon Rinsho Jpn J Clin Med 71(9):1597–1601Google Scholar
  25. 25.
    Nimkuntod P, Tongdee P (2015) Association between subclinical atherosclerosis among hyperlipidemia and healthy subjects. J Med Assoc Thailand 98(Suppl 4):S51–57Google Scholar
  26. 26.
    Navar-Boggan AM, Peterson ED, D’Agostino RB, Sr., Neely B, Sniderman AD, Pencina MJ (2015) Hyperlipidemia in early adulthood increases long-term risk of coronary heart disease. Circulation 131(5):451–458. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Dyson J, Day C (2014) Treatment of non-alcoholic fatty liver disease. Dig Dis 32(5):597–604. CrossRefPubMedGoogle Scholar
  28. 28.
    Ou HC, Song TY, Yeh YC, Huang CY, Yang SF, Chiu TH, Tsai KL, Chen KL, Wu YJ, Tsai CS, Chang LY, Kuo WW, Lee SD (2010) EGCG protects against oxidized LDL-induced endothelial dysfunction by inhibiting LOX-1-mediated signaling. J Appl Physio 108(6):1745–1756. CrossRefGoogle Scholar
  29. 29.
    Intra J, Kuo SM (2007) Physiological levels of tea catechins increase cellular lipid antioxidant activity of vitamin C and vitamin E in human intestinal caco-2 cells. Chem-Biol Interact 169(2):91–99. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Zhou P, Yu JF, Zhao CG, Sui FX, Teng X, Wu YB (2013) Therapeutic potential of EGCG on acute renal damage in a rat model of obstructive nephropathy. Mol Med Rep 7(4):1096–1102. CrossRefPubMedGoogle Scholar
  31. 31.
    Nakagawa T, Yokozawa T, Sano M, Takeuchi S, Kim M, Minamoto S (2004) Activity of (-)-epigallocatechin 3-O-gallate against oxidative stress in rats with adenine-induced renal failure. J Agric Food Chem 52(7):2103–2107. CrossRefPubMedGoogle Scholar
  32. 32.
    Koyama Y, Abe K, Sano Y, Ishizaki Y, Njelekela M, Shoji Y, Hara Y, Isemura M (2004) Effects of green tea on gene expression of hepatic gluconeogenic enzymes in vivo. Planta Med 70(11):1100–1102. CrossRefPubMedGoogle Scholar
  33. 33.
    Lee SJ, Sekimoto T, Yamashita E, Nagoshi E, Nakagawa A, Imamoto N, Yoshimura M, Sakai H, Chong KT, Tsukihara T, Yoneda Y (2003) The structure of importin-beta bound to SREBP-2: nuclear import of a transcription factor. Science 302(5650):1571–1575. CrossRefPubMedGoogle Scholar
  34. 34.
    Sato R (2009) SREBPs: protein interaction and SREBPs. FEBS J 276(3):622–627. CrossRefPubMedGoogle Scholar
  35. 35.
    Tamasawa N (2010) Disorder of cholesterol metabolism: regulation of intracellular cholesterol and membrane trafficking. Rinsho Byori Jpn J Clin Pathol 58(12):1203–1210Google Scholar
  36. 36.
    Singh AB, Kan CF, Dong B, Liu J (2016) SREBP2 activation induces hepatic long-chain Acyl-CoA synthetase 1 (ACSL1) expression in vivo and in vitro through a sterol regulatory element (SRE) motif of the ACSL1 C-promoter. J Biol Chem 291(10):5373–5384. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Eberle D, Hegarty B, Bossard P, Ferre P, Foufelle F (2004) SREBP transcription factors: master regulators of lipid homeostasis. Biochimie 86(11):839–848. CrossRefPubMedGoogle Scholar
  38. 38.
    Duncan MT, DeLuca TA, Kuo HY, Yi M, Mrksich M, Miller WM (2016) SIRT1 is a critical regulator of K562 cell growth, survival, and differentiation. Exp Cell Res 344(1):40–52. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Chini CC, Espindola-Netto JM, Mondal G, Guerrico AM, Nin V, Escande C, Sola-Penna M, Zhang JS, Billadeau DD, Chini EN (2016) SIRT1-activating compounds (STAC) negatively regulate pancreatic cancer cell growth and viability through a SIRT1 lysosomal-dependent pathway. Clin Cancer Res 22(10):2496–2507. CrossRefPubMedGoogle Scholar
  40. 40.
    Yan H, Wu A (2018) FOXO1 is crucial in glioblastoma cell tumorigenesis and regulates the expression of SIRT1 to suppress senescence in the brain. Mol Med Rep 17(2):2535–2542. PubMedGoogle Scholar
  41. 41.
    Imperatore F, Maurizio J, Vargas Aguilar S, Busch CJ, Favret J, Kowenz-Leutz E, Cathou W, Gentek R, Perrin P, Leutz A, Berruyer C, Sieweke MH (2017) SIRT1 regulates macrophage self-renewal. EMBO J 36(16):2353–2372. CrossRefPubMedGoogle Scholar
  42. 42.
    Deng X, Zhang W, I OS, Williams JB, Dong Q, Park EA, Raghow R, Unterman TG, Elam MB (2012) FoxO1 inhibits sterol regulatory element-binding protein-1c (SREBP-1c) gene expression via transcription factors Sp1 and SREBP-1c. J Biol Chem 287(24):20132–20143. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Tsunekawa S, Demozay D, Briaud I, McCuaig J, Accili D, Stein R, Rhodes CJ (2011) FoxO feedback control of basal IRS-2 expression in pancreatic beta-cells is distinct from that in hepatocytes. Diabetes 60(11):2883–2891. CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Biliary SurgeryShengjing Hospital of China Medical UniversityShenyangPeople’s Republic of China

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