Abstract
Liver disease associated with long-term drinking is one of the leading causes of death. There is an urgent need for more effective drugs to reduce alcoholic liver damage. Yin Chen Hao, a traditional Chinese herbal medicine, is widely used for liver diseases. Here, we aimed to explore the protective effect of β-sitosterol (the active ingredient of Artemisia spp.) on alcoholic liver injuries. We treated the rats with alcohol and different dosages of β-sitosterol to detect the expression levels of liver function indicators in serum. The functions of β-sitosterol were evaluated based on variations in histology, liver function indicators and DNA oxidative damages. The underlying mechanism was investigated by measuring lipid peroxidation, the antioxidant, the expression of cytochrome P450 2E1 and the expression of apoptosis related genes. The results showed that β-sitosterol could improve liver histology and suppress biochemical indicators caused by alcohol in serum. In addition, β-sitosterol alleviates alcohol-induced oxidative stress, such as restoring erythrocyte membrane fluidity, reducing glutathione depletion, restoring antioxidant enzyme activity and reducing malondialdehyde overproduction. Furthermore, β-sitosterol downregulated the expression of apoptosis-related genes through the PI3K/Akt pathway. In conclusion, β-sitosterol has a protective effect on chronic alcoholism and has broad clinical application prospects in the treatment of alcohol-induced liver damage.
Similar content being viewed by others
References
Addolorato G, Mirijello A, Barrio P, Gual A (2016) Treatment of alcohol use disorders in patients with alcoholic liver disease. J Hepatol 65:618–630. https://doi.org/10.1016/j.jhep.2016.04.029
Arteel GE (2003) Oxidants and antioxidants in alcohol-induced liver disease. Gastroenterology 124:778–790. https://doi.org/10.1053/gast.2003.50087
Ashakumary L, Vijayammal P (1996) Additive effect of alcohol and nicotine on lipid peroxidation and antioxidant defence mechanism in rats. J Appl Toxicol 16:305–308. https://doi.org/10.1002/(SICI)1099-1263(199607)1
Ayaz M, Junaid M, Ullah F, Subhan F, Sadiq A, Ali G, Ovais M, Shahid M, Ahmad A, Wadood A (2017) Anti-alzheimer’s studies on β-sitosterol isolated from polygonum hydropiper L. Front pharmacol 8:697. https://doi.org/10.3389/fphar.2017.00697
Bala S, Csak T, Saha B, Zatsiorsky J, Kodys K, Catalano D, Satishchandran A, Szabo G (2016) The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis. J Hepatol 64:1378–1387. https://doi.org/10.1016/j.jhep.2016.01.035
Brodie B, Butler W Jr, Horning M, Maickel R, Maling HM (1961) Alcohol-induced triglyceride deposition in liver through derangement of fat transport. Am J Clin Nutr 9:432–435. https://doi.org/10.1093/ajcn/9.4.432
Diehl AM, Potter J, Boitnott J, Van Duyn MA, Herlong HF, Mezey E (1984) Relationship between pyridoxal 5′-phosphate deficiency and aminotransferase levels in alcoholic hepatitis. Gastroenterology 86:632–636. https://doi.org/10.1016/S0016-5085(84)80110-9
Fernandez-Checa JC, Kaplowitz N, Colell A, Garcia-Ruiz C (1997) Oxidative stress and alcoholic liver disease. Alcohol Health Res World. 21:321–324. https://www.ncbi.nlm.nih.gov/pubmed/15706743.
Ferrere G, Wrzosek L, Cailleux F, Turpin W, Puchois V, Spatz M, Ciocan D, Rainteau D, Humbert L, Hugot C (2017) Fecal microbiota manipulation prevents dysbiosis and alcohol-induced liver injury in mice. J Hepatol 66:806–815. https://doi.org/10.1016/j.jhep.2016.11.008
Gao B, Bataller R (2011) Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterol 141:1572–1585. https://doi.org/10.1053/j.gastro.2011.09.002
Gupta M, Nath R, Srivastava N, Shanker K, Kishor K, Bhargava K (1980) Anti-inflammatory and antipyretic activities of β-sitosterol. Planta Med 39:157–163. https://doi.org/10.1055/s-2008-1074919
Gupta R, Sharma AK, Dobhal M, Sharma M, Gupta R (2011) Antidiabetic and antioxidant potential of β-sitosterol in streptozotocin-induced experimental hyperglycemia. J Diabetes 3:29–37. https://doi.org/10.1111/j.1753-0407.2010.00107.x
Gustot T, Fernandez J, Szabo G, Albillos A, Louvet A, Jalan R, Moreau R, Moreno C (2017) Sepsis in alcohol-related liver disease. J Hepatol 67:1031–1050. https://doi.org/10.1016/j.jhep.2017.06.013
Han D, Johnson HS, Rao MP, Martin G, Sancheti H, Silkwood KH, Decker CW, Nguyen KT, Casian JG, Cadenas E, Kaplowitz N (2017) Mitochondrial remodeling in the liver following chronic alcohol feeding to rats. Free Radic Biol Med 102:100–110. https://doi.org/10.1016/j.freeradbiomed.2016.11.020
Hirano A, Kaplowitz N, Tsukamoto H, Kamimura S, Fernandez-Checa JC (1992) Hepatic mitochondrial glutathione depletion and progression of experimental alcoholic liver disease in rats. Hepatology 16:1423–1427. https://doi.org/10.1002/hep.1840160619
Hu S, Yin S, Jiang X, Huang D, Shen G (2009) Melatonin protects against alcoholic liver injury by attenuating oxidative stress, inflammatory response, and apoptosis. Eur J Pharmacol 616:287–292. https://doi.org/10.1016/j.ejphar.2009.06.044
Hyder MA, Hasan M, Mohieldein AH (2013) Comparative levels of ALT, AST, ALP and GGT in liver associated diseases. Eur J Exp Biol 3:280–284
Kim WR, Flamm SL, Di Bisceglie AM, Bodenheimer HC (2008) Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease. Hepatology 47:1363–1370. https://doi.org/10.1002/hep.22109
Kitada T, Seki S, Iwai S, Yamada T, Sakaguchi H, Wakasa K (2001) In situ detection of oxidative DNA damage, 8-hydroxydeoxyguanosine, in chronic human liver disease. J Hepatol 35:613–618. https://doi.org/10.1016/s0168-8278(01)00171-4
Lackner C, Spindelboeck W, Haybaeck J, Douschan P, Rainer F, Terracciano L, Haas J, Berghold A, Bataller R, Stauber RE (2017) Histological parameters and alcohol abstinence determine long-term prognosis in patients with alcoholic liver disease. J Hepatol 66:610–618. https://doi.org/10.1016/j.jhep.2016.11.011
Leclercq IA, Farrell GC, Field J, Bell DR, Gonzalez FJ, Robertson GR (2000) CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J Clin Invest 105:1067–1075. https://doi.org/10.1172/JCI8814
Lee BP, Vittinghoff E, Hsu C, Han H, Therapondos G, Fix OK, Victor DW, Dronamraju D, Im GY, Voigt MD (2019) Predicting low risk for sustained alcohol use after early liver transplant for acute alcoholic hepatitis: the sustained alcohol use post-liver transplant score. Hepatology 69:1477–1487. https://doi.org/10.1002/hep.30478
Lee I-A, Kim E-J, Kim D-H (2012) Inhibitory effect of β-sitosterol on TNBS-induced colitis in mice. Planta Med 78:896–898. https://doi.org/10.1055/s-0031-1298486
Lieber CS (1993) Biochemical factors in alcoholic liver disease. Semin Liver Dis 13:136–153. https://doi.org/10.1055/s-2007-1007345
Lieber CS (1997) Role of oxidative stress and antioxidant therapy in alcoholic and nonalcoholic liver diseases. Adv Pharmacol 38:601–628. https://doi.org/10.1016/s1054-3589(08)61001-7
Loizou S, Lekakis I, Chrousos GP, Moutsatsou P (2010) β-Sitosterol exhibits anti-inflammatory activity in human aortic endothelial cells. Mol Nutri Food Res 54:551–558. https://doi.org/10.1002/mnfr.200900012
Mathiesen U, Franzen L, Frydén A, Foberg U, Bodemar G (1999) The clinical significance of slightly to moderately increased liver transaminase values in asymptomatic patients. Scand J Gastroenterol 34:85–91. https://doi.org/10.1080/00365529950172880
Matloff DS, Selinger MJ, Kaplan MM (1980) Hepatic transaminase activity in alcoholic liver disease. Gastroenterology 78:1389–1392. https://doi.org/10.1016/S0016-5085(19)30490-1
Muti P, Awad AB, SchüNemann H, Fink CS, Hovey K, Freudenheim JL, Wu Y-WB, Bellati C, Pala V, Berrino F (2003) A plant food–based diet modifies the serum β-sitosterol concentration in hyperandrogenic postmenopausal women. J Nutr 133:4252–4255. https://doi.org/10.1093/jn/133.12.4252
Rogers KS (1972) Variable sulfhydryl activity toward silver nitrate by reduced glutathione and alcohol, glutamate and lactate dehydrogenases. Biochim Biophys Acta Proteins Structure. 263:309–314. https://doi.org/10.1016/0005-2795(72)90084-0
Salen G, Ahrens E, Grundy SM (1970) Metabolism of β-sitosterol in man. J Clin Invest 49:952–967. https://doi.org/10.1172/JCI106315
Sorbi D, Boynton J, Lindor KD (1999) The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease. Am J Gastroenterol 94:1018. https://doi.org/10.1111/j.1572-0241.1999.01006.x
Stickel F, Schuppan D (2007) Herbal medicine in the treatment of liver diseases. Dig Liver Dis 39:293–304. https://doi.org/10.1016/j.dld.2006.11.004
Suematsu T, Matsumura T, Sato N, Miyamoto T, Ooka T, Kamada T, Abe H (1981) Lipid peroxidation in alcoholic liver disease in humans. Alcohol Clin Exp Res 5:427–430. https://doi.org/10.1111/j.1530-0277.1981.tb04926.x
Tamburello A, Marando M, Bellentani S (2018) Alcohol consumption in late adolescence is associated with an increased risk of severe liver disease later in life. Annal Hepatol 17:343–344. https://doi.org/10.1016/j.jhep.2017.11.019
Vivancos M, Moreno JJ (2005) β-Sitosterol modulates antioxidant enzyme response in RAW 264.7 macrophages. Free Radic Biol Med 39:91–97. https://doi.org/10.1016/j.freeradbiomed.2005.02.025
Wang X, Lv H, Sun H, Liu L, Yang B, Sun W, Wang P, Zhou D, Zhao L, Dou S (2008) Metabolic urinary profiling of alcohol hepatotoxicity and intervention effects of Yin Chen Hao Tang in rats using ultra-performance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry. J Pharm Biomed Anal 48:1161–1168. https://doi.org/10.1016/j.jpba.2008.07.028
Wheeler MD, Nakagami M, Bradford BU, Uesugi T, Mason RP, Connor HD, Dikalova A, Kadiiska M, Thurman RG (2001) Overexpression of manganese superoxide dismutase prevents alcohol-induced liver injury in the rat. J Biol Chem 276:36664–36672. https://doi.org/10.1074/jbc.M105352200
Yamada S, Mak KM, Lieber CS (1985) Chronic ethanol consumption alters rat liver plasma membranes and potentiates release of alkaline phosphatase. Gastroenterology 88:1799–1806. https://doi.org/10.1016/0016-5085(85)90003-4
Zhao J, Chen H, Li Y (2008) Protective effect of bicyclol on acute alcohol-induced liver injury in mice. Eur J Pharmacol 586:322–331. https://doi.org/10.1016/j.ejphar.2008.02.059
Zhou Z, Sun X, Lambert JC, Saari JT, Kang YJ (2002) Metallothionein-independent zinc protection from alcoholic liver injury. Am J Pathol 160:2267–2274. https://doi.org/10.1016/S0002-9440(10)61174-1
Acknowledgements
Not applicable.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The author reports no conflicts of interest in this work.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Chen, Z., Wu, A., Jin, H. et al. β-Sitosterol attenuates liver injury in a rat model of chronic alcohol intake. Arch. Pharm. Res. 43, 1197–1206 (2020). https://doi.org/10.1007/s12272-020-01271-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-020-01271-w