Browse > Article
http://dx.doi.org/10.4014/jmb.1707.07061

Fermented Soymilk Alleviates Lipid Accumulation by Inhibition of SREBP-1 and Activation of NRF-2 in the Hepatocellular Steatosis Model  

Ahn, Sang Bong (Department of Internal Medicine, Eulji University School of Medicine)
Wu, Wen Hao (Eulji Medi-Bio Research Institute (EMBRI), Eulji University)
Lee, Jong Hun (Eulji Medi-Bio Research Institute (EMBRI), Eulji University)
Jun, Dae Won (Department of Internal Medicine, Hanyang University College of Medicine)
Kim, Jihyun (Department of Senior Healthcare, BK21 Plus Program, Graduate School of Eulji University)
Kim, Riji (Department of Senior Healthcare, BK21 Plus Program, Graduate School of Eulji University)
Lee, Tae-bok (Department of Senior Healthcare, BK21 Plus Program, Graduate School of Eulji University)
Jun, Jin Hyun (Eulji Medi-Bio Research Institute (EMBRI), Eulji University)
Publication Information
Journal of Microbiology and Biotechnology / v.28, no.2, 2018 , pp. 236-245 More about this Journal
Abstract
Ingredients of soy and fermented soy products have been widely utilized as food supplements for health-enhancing properties. The aim of this study was to evaluate the effects of fermented soymilk (FSM) and soymilk (SM) on free fatty acid-induced lipogenesis in the hepatocellular steatosis model. HepG2 cells were incubated with palmitic acid (PA) for 24 h to induce lipogenesis and accumulation of intracellular lipid contents. The PA-treated cells were co-incubated with FSM, SM, genistein, and estrogen, respectively. Lipid accumulation in the PA-treated HpG2 cells was significantly decreased by co-incubation with FSM. Treatment of HepG2 cells with PA combined with genistein or estrogen significantly increased the expression of SREBP-1. However, FSM co-incubation significantly attenuated SREBP-1 expression in the PA-treated HepG2 cells; in addition, expression of NRF-2 and phosphorylation of ERK were significantly increased in the PA and FSM co-incubated cells. PA-induced ROS production was significantly reduced by FSM and SM. Our results suggested that the bioactive components of FSM could protect hepatocytes against the lipid accumulation and ROS production induced by free fatty acids. These effects may be mediated by the inhibition of SREBP-1 and the activation of NRF-2 via the ERK pathway in HepG2 cells.
Keywords
Fermented soymilk; steatosis model; HepG2; SREBP-1; NRF-2;
Citations & Related Records
Times Cited By KSCI : 3  (Citation Analysis)
연도 인용수 순위
1 Shaker M, Tabbaa A, Albeldawi M, Alkhouri N. 2014. Liver transplantation for nonalcoholic fatty liver disease: new challenges and new opportunities. World J. Gastroenterol. 20: 5320-5330.   DOI
2 Rinella ME. 2015. Nonalcoholic fatty liver disease: a systematic review. JAMA 313: 2263-2273.   DOI
3 Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. 2004. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40: 1387-1395.   DOI
4 Lavine JE, Schwimmer JB. 2004. Nonalcoholic fatty liver disease in the pediatric population. Clin. Liver Dis. 8: 549-558, viii-ix.
5 Reddy JK, Rao MS. 2006. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am. J. Physiol. Gastrointest. Liver Physiol. 290: G852-G858.
6 Farrell GC, Larter CZ. 2006. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 43: S99-S112.   DOI
7 Durazzo M, Belci P, Collo A, Grisoglio E, Bo S. 2012. Focus on therapeutic strategies of nonalcoholic fatty liver disease. Int. J. Hepatol. 2012: 464706.
8 Leamy AK, Egnatchik RA, Young JD. 2013. Molecular mechanisms and the role of saturated fatty acids in the progression of non-alcoholic fatty liver disease. Prog. Lipid Res. 52: 165-174.   DOI
9 Malhi H, Barreyro FJ, Isomoto H, Bronk SF, Gores GJ. 2007. Free fatty acids sensitise hepatocytes to TRAIL mediated cytotoxicity. Gut 56: 1124-1131.   DOI
10 Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, Lindor KD, et al. 2003. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 125: 437-443.   DOI
11 Kim NH, Moon PD, Kim SJ, Choi IY, An HJ, Myung NY, et al. 2008. Lipid profile lowering effect of Soypro fermented with lactic acid bacteria isolated from kimchi in high-fat dietinduced obese rats. Biofactors 33: 49-60.   DOI
12 Kaizu H, Sasaki M, Nakajima H, Suzuki Y. 1993. Effect of antioxidative lactic acid bacteria on rats fed a diet deficient in vitamin E. J. Dairy Sci. 76: 2493-2499.
13 Perdigon G, Naderde Macias ME, Alvarez S, Oliver G, Pesce de Ruiz Holgado AA. 1990. Prevention of gastrointestinal infection using immunobiological methods with milk fermented with Lactobacillus casei and Lactobacillus acidophilus. J. Dairy Res. 57: 255-264.   DOI
14 Shahani KM, Ayebo AD. 1980. Role of dietary lactobacilli in gastrointestinal microecology. Am. J. Clin. Nutr. 33: 2448-2457.   DOI
15 Choi YM, Bae SH, Kang DH, Suh HJ. 2006. Hypolipidemic effect of lactobacillus ferment as a functional food supplement. Phytother. Res. 20: 1056-1060.   DOI
16 Shida K, Makino K, Morishita A, Takamizawa K, Hachimura S, Ametani A, et al. 1998. Lactobacillus casei inhibits antigeninduced IgE secretion through regulation of cytokine production in murine splenocyte cultures. Int. Arch. Allergy Immunol. 115: 278-287.   DOI
17 Liu JR, Wang SY, Chen MJ, Chen HL, Yueh PY, Lin CW. 2006. Hypocholesterolaemic effects of milk-kefir and soyamilkkefir in cholesterol-fed hamsters. Br. J. Nutr. 95: 939-946.   DOI
18 Park DJ, Oh S, Ku KH, Mok C, Kim SH, Imm JY. 2005. Characteristics of yogurt-like products prepared from the combination of skim milk and soymilk containing saccharifiedrice solution. Int. J. Food Sci. Nutr. 56: 23-34.   DOI
19 Kang MS, Rhee YH. 1996. Physico-chemical characteristics and ${\beta}$-galactosidase activity of Lactobacillus plantarum from kimchi. J. Korean Soc. Appl. Biol. Chem. 39: 54-59.
20 Lin FM, Chiu CH, Pan TM. 2004. Fermentation of a milksoymilk and Lycium chinense Miller mixture using a new isolate of Lactobacillus paracasei subsp. paracasei NTU101 and Bifidobacterium longum. J. Ind. Microbiol. Biotechnol. 31: 559-564.
21 Chen K, Li S, Chen F, Li J, Luo X. 2016. Regulation of the Lactobacillus strains on HMGCoA reductase gene transcription in human HepG2 cells via nuclear factor-${\kappa}B$. J. Microbiol. Biotechnol. 26: 402-407.   DOI
22 Kim AH, K im H J, Ryu R , Han HJ, Han YJ, Choi M S, et al. 2016. A mixture of ethanol extracts of persimmon leaf and Citrus junos Sieb improves blood coagulation parameters and ameliorates lipid metabolism disturbances caused by diet-induced obesity in C57BL/6J mice. J. Microbiol. Biotechnol. 26: 295-308.   DOI
23 Kang S, Lee JS, Lee HC, Petriello MC, Kim BY, Do JT, et al. 2016. Phytoncide extracted from pinecone decreases LPSinduced inflammatory responses in bovine mammary epithelial cells. J. Microbiol. Biotechnol. 26: 579-587.   DOI
24 Donohue TM Jr. 2007. Alcohol-induced steatosis in liver cells. World J. Gastroenterol. 13: 4974-4978.   DOI
25 Tezuka H, Imai S. 2015. Immunomodulatory effects of soybeans and processed soy food compounds. Recent Pat. Food Nutr. Agric. 7: 92-99.   DOI
26 Kim JH, Chen C, Kong ANT. 2011. Resveratrol inhibits genistein-induced multi-drug resistance protein 2 (MRP2) expression in HepG2 cells. Arch. Biochem. Biophys. 512: 160-166.   DOI
27 Kelly LA, Seidlova-Wuttke D, Wuttke W, O’Leary JJ, Norris LA. 2014. Estrogen receptor alpha augments changes in hemostatic gene expression in HepG2 cells treated with estradiol and phytoestrogens. Phytomedicine 21: 155-158.   DOI
28 Smutny T, Bitman M, Urban M, Dubecka M, Vrzal R, Dvorak Z, et al. 2014. U0126, a mitogen-activated protein kinase kinase 1 and 2 (MEK1 and 2) inhibitor, selectively up-regulates main isoforms of CYP3A subfamily via a pregnane X receptor (PXR) in HepG2 cells. Arch. Toxicol. 88: 2243-2259.
29 Imai S. 2015. Functional properties of soybean and processed soy foods ingredients. Recent Pat. Food Nutr. Agric. 7: 74.   DOI
30 Kersten S. 2001. Mechanisms of nutritional and hormonal regulation of lipogenesis. EMBO Rep. 2: 282-286.   DOI
31 Zhang EJ, Ng KM, Luo KQ. 2007. Extraction and purification of isoflavones from soybeans and characterization of their estrogenic activities. J. Agric. Food Chem. 55: 6940-6950.
32 Sakai T, Kogiso M. 2008. Soy isoflavones and immunity. J. Med. Invest. 55: 167-173.   DOI
33 Mohamed SS, Nallasamy P, Muniyandi P, Periyasami V, Carani VA. 2009. Genistein improves liver function and attenuates non-alcoholic fatty liver disease in a rat model of insulin resistance. J. Diabetes 1: 278-287.   DOI
34 Houghton CA, Fassett RG, Coombes JS. 2016. Sulforaphane and other nutrigenomic Nrf2 activators: can the clinician's expectation be matched by the reality? Oxid. Med. Cell. Longev. 2016: 7857186.
35 Ferre P, Foufelle F. 2010. Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c. Diabetes Obes. Metab. 12 Suppl 2: 83-92.   DOI
36 Eberle D, Hegarty B, Bossard P, Ferre P, Foufelle F. 2004. SREBP transcription factors: master regulators of lipid homeostasis. Biochimie 86: 839-848.   DOI
37 Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al. 2012. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N. Engl. J. Med. 367: 1098-1107.   DOI
38 Balkwill F, M antovani A. 2001. Iflammation and cancer: back to Virchow? Lancet 357: 539-545.
39 Yang Y, Cai X, Yang J, Sun X, Hu C, Yan Z, et al. 2014. Chemoprevention of dietary digitoflavone on colitis-associated colon tumorigenesis through inducing Nrf2 signaling pathway and inhibition of inflammation. Mol. Cancer 13: 48.   DOI
40 Klaunig JE, Wang Z, Pu X, Zhou S. 2011. Oxidative stress and oxidative damage in chemical carcinogenesis. Toxicol. Appl. Pharmacol. 254: 86-99.
41 Lee JS, Surh YJ. 2005. Nrf2 as a novel molecular target for chemoprevention. Cancer Lett. 224: 171-184.   DOI
42 Sharma S, Stutzman JD, Kelloff GJ, Steele VE. 1994. Screening of potential chemopreventive agents using biochemical markers of carcinogenesis. Cancer Res. 54: 5848-5855.
43 Cerutti PA. 1985. Prooxidant states and tumor promotion. Science 227: 375-381.   DOI
44 Roskoski R Jr. 2012. ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol. Res. 66: 105-143.   DOI
45 Froyen EB, Steinberg FM. 2011. Soy isoflavones increase quinone reductase in hepa-1c1c7 cells via estrogen receptor beta and nuclear factor erythroid 2-related factor 2 binding to the antioxidant response element. J. Nutr. Biochem. 22: 843-848.   DOI
46 Setchell KD, Clerici C, Lephart ED, Cole SJ, Heenan C, Castellani D, et al. 2005. S-equol, a potent ligand for estrogen receptor beta, is the exclusive enantiomeric form of the soy isoflavone metabolite produced by human intestinal bacterial flora. Am. J. Clin. Nutr. 81: 1072-1079.   DOI
47 Zhang T, Liang X, Shi L, Wang L, Chen J, Kang C, et al. 2013. Estrogen receptor and PI3K/Akt signaling pathway involvement in S-(-)equol-induced activation of Nrf2/ARE in endothelial cells. PLoS One 8: e79075.
48 Knebel B, Lehr S, Hartwig S, Haas J, Kaber G, Dicken HD, et al. 2014. Phosphorylation of sterol regulatory elementbinding protein (SREBP)-1c by p38 kinases, ERK and JNK influences lipid metabolism and the secretome of human liver cell line HepG2. Arch. Physiol. Biochem. 120: 216-227.   DOI
49 Kotzka J, Muller-Wieland D, Roth G, Kremer L, Munck M, Schurmann S, et al. 2000. Sterol regulatory element binding proteins (SREBP)-1a and SREBP-2 are linked to the MAPkinase cascade. J. Lipid Res. 41: 99-108.