Abstract
One pathogenic mechanism of ethanol-induced liver injury is the excessive production of reactive oxygen species (ROS), which may result in alcoholic liver disease (ALD) characterized by cell death due to necrosis and apoptosis. Taurine was proved to protect against liver damage. However, whether taurine attenuates ethanol-induced hepatic apoptosis remains unknown. The present study aims to elucidate this effect and its underlying mechanism. Taurine was administered to ALD rats and an in vitro experiment in which taurine was added to primary rat hepatocytes cultured with ethanol was conducted. Mitochondrial function and anti-oxidative capacity of the liver were tested. TUNEL and AO-EB double staining were conducted to detect apoptosis of liver cells. Expressions of factors and proteins involved in mitochondrial and death receptor pathways were detected by RT-PCR and Western-blot. The results showed that taurine inhibited the decline of cell functions and apoptosis in hepatocytes cultured with ethanol. Furthermore, increased malondialdehyde (MDA) and reduced superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC), cytochrome c oxidase (COX) and NADH dehydrogenase (ND) in ALD rats were mediated by taurine. RT-PCR and western-blot results revealed that taurine down-regulated expression of Bax, Fas, Fas ligand (FasL), caspase 3 and caspase 9 while up-regulating the expression of Bcl-2 in ethanol-cultured hepatocytes. In summary, taurine inhibit ethanol-induced hepatic apoptosis by regulating mitochondrial or death receptor pathways.
Graphical abstract
Similar content being viewed by others
References
Allam RM et al (2013) Hepatoprotective effects of Astragalus kahiricus root extract against ethanol-induced liver apoptosis in rats. Chin J Nat Med 11:354–361
Aly HA, Khafagy RM (2014) Taurine reverses endosulfan-induced oxidative stress and apoptosis in adult rat testis. Food Chem Toxicol 64:1–9
Aydin AF, Coban J, Dogan-Ekici I, Betul-Kalaz E, Dogru-Abbasoglu S, Uysal M (2016) Carnosine and taurine treatments diminished brain oxidative stress and apoptosis in d-galactose aging model. Metab Brain Dis 31:337–345
Balkan J, Kanbagli O, Aykac-Toker G, Uysal M (2002) Taurine treatment reduces hepatic lipids and oxidative stress in chronically ethanol-treated rats. Biol Pharm Bull 25:1231–1233
Basaran-Kucukgergin C, Bingul I, Tekkesin MS, Olgac V, Dogru-Abbasoglu S, Uysal M (2016) Effects of carnosine, taurine, and betaine pretreatments on diethylnitrosamine-induced oxidative stress and tissue injury in rat liver. Toxicol Ind Health 32:1405–1413
Chen X, Sebastian BM, Tang H, McMullen MM, Axhemi A, Jacobsen DW, Nagy LE (2009) Taurine supplementation prevents ethanol-induced decrease in serum adiponectin and reduces hepatic steatosis in rats. Hepatology 49:1554–1562
Darwish HA, Abd Raboh NR, Mahdy A (2012) Camel’s milk alleviates alcohol-induced liver injury in rats. Food Chem Toxicol 50:1377–1383
Das J, Ghosh J, Manna P, Sil PC (2010) Protective role of taurine against arsenic-induced mitochondria-dependent hepatic apoptosis via the inhibition of PKCdelta-JNK pathway. PLoS One 5:e12602. https://doi.org/10.1371/journal.pone.0012602
Devi SL, Viswanathan P, Anuradha CV (2009) Taurine enhances the metabolism and detoxification of ethanol and prevents hepatic fibrosis in rats treated with iron and alcohol. Environ Toxicol Pharmacol 27:120–126
Dillon JF, Miller MH (2016) Gamma glutamyl transferase ‘To be or not to be’ a liver function test? Ann Clin Biochem 53:629–631
Erman F, Balkan J, Cevikbas U, Kocak-Toker N, Uysal M (2004) Betaine or taurine administration prevents fibrosis and lipid peroxidation induced by rat liver by ethanol plus carbon tetrachloride intoxication. Amino Acids 27:199–205
Heaton MB, Paiva M, Siler-Marsiglio K (2011) Ethanol influences on Bax translocation, mitochondrial membrane potential, and reactive oxygen species generation are modulated by vitamin E and brain-derived neurotrophic factor. Alcohol Clin Exp Res 35:1122–1133
Hoek JB, Pastorino JG (2002) Ethanol, oxidative stress, and cytokine-induced liver cell injury. Alcohol 27:63–68
Jia N, Sun Q, Su Q, Dang S, Chen G (2016) Taurine promotes cognitive function in prenatally stressed juvenile rats via activating the Akt-CREB-PGC1alpha pathway. Redox Biol 10((C)):179–190
Jong CJ, Azuma J, Schaffer SW (2011) Role of mitochondrial permeability transition in taurine deficiency-induced apoptosis. Exp Clin Cardiol 16:125–128
Jong CJ, Azuma J, Schaffer S (2012) Mechanism underlying the antioxidant activity of taurine: prevention of mitochondrial oxidant production. Amino Acids 42:2223–2232
Jong CJ, Ito T, Prentice H, Wu JY, Schaffer SW (2017) Role of mitochondria and endoplasmic reticulum in taurine-deficiency-mediated apoptosis. Nutrients. https://doi.org/10.3390/nu9080795
Lakshmi Devi S, Anuradha CV (2010) Mitochondrial damage, cytotoxicity and apoptosis in iron-potentiated alcoholic liver fibrosis: amelioration by taurine. Amino Acids 38:869–879
Lambert JC, Zhou Z, Kang YJ (2003) Suppression of Fas-mediated signaling pathway is involved in zinc inhibition of ethanol-induced liver apoptosis. Exp Biol Med (Maywood) 228:406–412
Lee SY, Ko KS (2016) Effects of S-adenosylmethionine and its combinations with taurine and/or betaine on glutathione homeostasis in ethanol-induced acute hepatotoxicity. J Cancer Prev 21:164–172
Lee YY et al (2011) Taurine supplementation restored the changes in pancreatic islet mitochondria in the fetal protein-malnourished rat. Br J Nutr 106:1198–1206
Lee SJ, Kim SY, Min H (2013) Effects of vitamin C and E supplementation on oxidative stress and liver toxicity in rats fed a low-fat ethanol diet. Nutr Res Pract 7:109–114
Li S et al (2017) Taurine inhibits 2,5-hexanedione-induced oxidative stress and mitochondria-dependent apoptosis in PC12 cells. Ind Health 55:108–118
Liu J (2004) Fas-mediated signaling pathway in ethanol-induced liver apoptosis: inhibition by zinc. Exp Biol Med (Maywood) 229:365–366
Liu J, Zhou J, Wu Z, Wang X, Liu L, Yao C (2016) Cyanidin 3-O-β-glucoside ameliorates ethanol-induced acute liver injury by attenuating oxidative stress and apoptosis: the role of SIRT1/FOXO1 signaling. Alcohol Clin Exp Res 40:457–466
Livero FA, Acco A (2016) Molecular basis of alcoholic fatty liver disease: from incidence to treatment. Hepatol Res 46:111–123
Ma Z, Hou T, Shi W, Liu W, He H (2015) Inhibition of hepatocyte apoptosis: an important mechanism of corn peptides attenuating Liver injury induced by ethanol. Int J Mol Sci 16:22062–22080
Mcclain CJ, Song Z, Barve SS, Hill DB, Deaciuc I (2004) Recent advances in alcoholic liver disease. IV. Dysregulated cytokine metabolism in alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol 287:497–502
McVicker BL, Tuma DJ, Kubik JL, Tuma PL, Casey CA (2006) Ethanol-induced apoptosis in polarized hepatic cells possibly through regulation of the Fas pathway. Alcohol Clin Exp Res 30:1906–1915
Mo XQ et al (2017) Molecular mechanisms of apoptosis in hepatocellular carcinoma cells induced by ethanol extracts of Solanum lyratum Thumb through the mitochondrial pathway. World J Gastroenterol 23:1010–1017
Morio Y et al (2013) Ethanol-induced apoptosis in human liver adenocarcinoma cells (SK-Hep1): fas- and mitochondria-mediated pathways and interaction with MAPK signaling system. Toxicol In Vitro 27:1820–1829
Nagai K, Fukuno S, Oda A, Konishi H (2016) Protective effects of taurine on doxorubicin-induced acute hepatotoxicity through suppression of oxidative stress and apoptotic responses. Anticancer Drugs 27:17–23
Reeta KH, Singh D, Gupta YK (2017) Chronic treatment with taurine after intracerebroventricular streptozotocin injection improves cognitive dysfunction in rats by modulating oxidative stress, cholinergic functions and neuroinflammation. Neurochem Int 108:146–156
Revollo JR, Li X (2013) The ways and means that fine tune Sirt1 activity. Trends Biochem Sci 38:160
Ronis MJ et al (2005) Effects of N-acetylcysteine on ethanol-induced hepatotoxicity in rats fed via total enteral nutrition. Free Radic Biol Med 39:619–630
Shao A, Hathcock JN (2008) Risk assessment for the amino acids taurine, l-glutamine and l-arginine. Regul Toxicol Pharmacol 50:376–399
Sun Q, Zhang W, Zhong W, Sun X, Zhou Z (2017) Pharmacological inhibition of NOX4 ameliorates alcohol-induced liver injury in mice through improving oxidative stress and mitochondrial function. Biochim Biophys Acta 1861:2912–2921
Vijayalakshmi A, Sindhu G (2017) Umbelliferone arrest cell cycle at G0/G1 phase and induces apoptosis in human oral carcinoma (KB) cells possibly via oxidative DNA damage. Biomed Pharmacother 92:661–671
Wu G, Yang J, Sun C, Luan X, Shi J, Hu J (2009) Effect of taurine on alcoholic liver disease in rats. Amino Acids 36:457–464
Xie X, Xu X, Sun C, Yu Z (2018) Protective effects of cilostazol on ethanol-induced damage in primary cultured hepatocytes. Cell Stress Chaperones 23:203–211
Yalcinkaya S, Unlucerci Y, Giris M, Olgac V, Dogru-Abbasoglu S, Uysal M (2009) Oxidative and nitrosative stress and apoptosis in the liver of rats fed on high methionine diet: protective effect of taurine. Nutrition 25:436–444
Yang J, Zong X, Wu G, Lin S, Feng Y, Hu J (2015) Taurine increases testicular function in aged rats by inhibiting oxidative stress and apoptosis. Amino Acids 47:1549–1558
Yildirim Z, Kilic N, Ozer C, Babul A, Take G, Erdogan D (2007) Effects of taurine in cellular responses to oxidative stress in young and middle-aged rat liver. Ann N Y Acad Sci 1100:553–561
Zhou Z, Sun X, Kang YJ (2001) Ethanol-induced apoptosis in mouse liver: fas- and cytochrome c-mediated caspase-3 activation pathway. Am J Pathol 159:329–338
Acknowledgements
This work was supported by the National Natural Science Foundation of China (Nos. 31772694, 31302051 and 31172285).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.
Research involving human participants and/or animals
All procedures using animals were conducted according to the requirements of the Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals. The procedures were approved by the Animal Care and Use Committee of Shenyang Agricultural University (No. 20141013).
Rights and permissions
About this article
Cite this article
Wu, G., Yang, J., Lv, H. et al. Taurine prevents ethanol-induced apoptosis mediated by mitochondrial or death receptor pathways in liver cells. Amino Acids 50, 863–875 (2018). https://doi.org/10.1007/s00726-018-2561-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-018-2561-3