Gallic acid treats dust-induced NAFLD in rats by improving the liver’s anti-oxidant capacity and inhibiting ROS/NFκβ/TNFα inflammatory pathway

Document Type : Original Article


1 Physiology Research Center (PRC), Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

2 Persian Gulf’s Physiology Research Center (PRC), Department of Physiology, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

3 Air Pollution and Respiratory Diseases Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Environmental Technologies Research Center (ETRC), Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

4 Cellular and Molecular Research Center, Department of Anatomical Science, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran


Objective(s): The burden of disease and death related to environmental pollution is becoming a major public health challenge, especially in developing countries. This study was designed to investigate the effect of dust exposure on liver function and its structure in rats. Gallic acid (GA) as a potent anti-oxidant was also used to treat NAFLD in rats exposed to dust.
Materials and Methods: Twenty-four rats were randomly assigned into 3 groups: CA, Dust+N/S (after stopping dust exposure, rats received normal saline as vehicle, 1 ml, orally for 14 consecutive days), and Dust+GA (after stopping dust exposure, rats received GA at 100 mg/kg, orally for 14 consecutive days). Rats were exposed to CA/ dust for 6 weeks on alternate days. At the end of experiments, rats were anesthetized, their blood samples and liver sections were taken to perform molecular, biomedical and histopathological evaluations.
Results: Dust exposure induced NAFLD features in rats. It increased the serum levels of liver enzymes, LDL, TG, cholesterol, MDA, and mRNA expression of NFκβ, TNFα, IL-6, HO1, and miRs [122 and 34a], while decreasing serum levels of HDL and liver TAC. Treatment with GA improved liver enzymes, serum levels of miRs, TG, expression of NFκβ, TNFα, IL-6, Nrf2, and HO1 and liver MDA and TAC levels, while it could not improve HDL, LDL, and cholesterol.
Conclusion: This study showed dust exposure induced NAFLD in Wistar rats through inducing oxidative stress. Oxidative stress through activating the inflammatory pathways caused NAFLD features. Gallic acid treatment by inhibiting oxidative stress effectively protected liver function against dust induced inflammation.


1. Kampa M, Castanas E. Human health effects of air pollution. Environ Pollut. 2008;151:362-367.
2. Poschl U. Atmospheric aerosols: composition, transformation, climate and health effects. Angew Chem Int Ed Engl 2005;44:7520-7540.
3. Al-Taiar A, Thalib L. Short-term effect of dust storms on the risk of mortality due to respiratory, cardiovascular and all-causes in Kuwait. Int J Biometeorol 2014;58:69-77.
4. Goudie AS, Middleton NJ. The changing frequency of dust stormsthrough time. Clim Change 2006; 20:167-191.
5. Zauli Sajani S, Miglio R, Bonasoni P, Cristofanelli P, Marinoni A, Sartini C, et al. Saharan dust and daily mortality in Emilia-Romagna (Italy). Occup Environ Med 2011;68:446-451.
6. Gonzalez-Martin C, Teigell-Perez N, Valladares B, Griffin DW. The global dispersion of pathogenic microorganisms by dust storms and its relevance to agriculture. Adv Agron 2014;127:1-41.
7. Washington R, Todd M, J.Middleton N, S.Goudie A. Dust storm source areas determined by the total ozone monitoring spectrometer and surface observations. Ann Am Assoc Geogr 2003; 93:297-313.
8.    Zheng Z, Zhang X, Wang J, Dandekar A, Kim H, Qiu Y, et al. Exposure to fine airborne particulate matters induces hepatic fibrosis in murine models. J Hepatol 2015;63:1397-1404.
9. Tan H-H, Fiel MI, Sun Q, Guo J, Gordon RE, Chen L-C, et al. Kupffer cell activation by ambient air particulate matter exposure may exacerbate non-alcoholic fatty liver disease. J Immunotoxicol 2009;6:266-275.
10.    Brunt EM, editor Nonalcoholic steatohepatitis: definition and pathology. Seminars in liver disease; 2001: Copyright© 2001 by Thieme Medical Publishers, Inc., 333 Avenue
11.    Li R, Zhang M, Wang Y, Yung KKL, Su R, Li Z, et al. Effects of sub-chronic exposure to atmospheric PM 2.5 on fibrosis, inflammation, endoplasmic reticulum stress and apoptosis in the livers of rats. Toxico Res 2018;7:271-282.
12.    Araujo JA, Barajas B, Kleinman M, Wang X, Bennett BJ, Gong KW, et al. Ambient particulate pollutants in the ultrafine range promote early atherosclerosis and systemic oxidative stress. Circ Res 2008;102:589-596.
13.    Jang A, Srinivasan P, Lee NY, Song HP, Lee JW, Lee M, et al. Comparison of hypolipidemic activity of synthetic gallic acid–linoleic acid ester with mixture of gallic acid and linoleic acid, gallic acid, and linoleic acid on high-fat diet induced obesity in C57BL/6 Cr Slc mice. Chem Biolo Interact 2008;174:109-117.
14.    Ryter SW, Alam J, Choi AM. Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol ReV 2006;86:583-650.
15.    Bernardi C, Soffientini U, Piacente F, Tonetti MG. Effects of microRNAs on fucosyltransferase 8 (FUT8) expression in hepatocarcinoma cells. PLoS One 2013;8:e76540.
16.    Siaj R, Sauer V, Stoppeler S, Gerss J, Spiegel HU, Kohler G, et al. Longitudinal analysis of serum miR-122 in a rat model of Wilson’s disease. Hepatol Int 2012;6:770-777.
17.    McDaniel K, Herrera L, Zhou T, Francis H, Han Y, Levine P, et al. The functional role of microRNAs in alcoholic liver injury. J Cell Mol Med 2014;18:197-207.
18.    Maheshwari DT, Yogendra Kumar MS, Verma SK, Singh VK, Singh SN. Anti-oxidant and hepatoprotective activities of phenolic rich fraction of Seabuckthorn (Hippophae rhamnoides L.) leaves. Food Chem Toxicol 2011;49:2422-2428.
19.    Chao J, Huo T-I, Cheng H-Y, Tsai J-C, Liao J-W, Lee M-S, et al. Gallic acid ameliorated impaired glucose and lipid homeostasis in high fat diet-induced NAFLD mice. PLoS One 2014;9:e96969.
20.    Wang S-H, Kao M-Y, Wu S-C, Lo D-Y, Wu J-Y, Chang J-C, et al. Oral administration of Trapa taiwanensis Nakai fruit skin extracts conferring hepatoprotection from CCl4-caused injury. J Agric Food Chem 2011;59:3686-3692.
21.    Lee J-E, Lee B-J, Hwang J-a, Ko K-S, Chung J-O, Kim E-H, et al. Metabolic dependence of green tea on plucking positions revisited: A metabolomic study. J Agric Food Chem 2011;59:10579-10585.
22.    Ma J, Luo X-D, Protiva P, Yang H, Ma C, Basile MJ, et al. Bioactive novel polyphenols from the fruit of Manilkara zapota (Sapodilla). Jof Nat Prod 2003;66:983-986.
23.    Oi Y, Hou IC, Fujita H, Yazawa K. Antiobesity effects of Chinese black tea (pu-erh tea) extract and gallic acid. Phytother Res 2012;26:475-481.
24.    Hsiang C-Y, Hseu Y-C, Chang Y-C, Kumar KS, Ho T-Y, Yang H-L. Toona sinensis and its major bioactive compound gallic acid inhibit LPS-induced inflammation in nuclear factor-κB transgenic mice as evaluated by in vivo bioluminescence imaging. Food Chemistry 2013;136:426-434.
25.    Chao J, Huo TI, Cheng HY, Tsai JC, Liao JW, Lee MS, et al. Gallic acid ameliorated impaired glucose and lipid homeostasis in high fat diet-induced NAFLD mice. PLoS One 2014;9:e96969.
26.    Heidari-Farsani M, Shirmardi M, Goudarzi G, Alavi-Bakhtiarivand N, Ahmadi-Ankali K, Zallaghi E, et al. The evaluation of heavy metals concentration related to PM10 in ambient air of Ahvaz city, Iran. JAEHR 2013;1:120-128.
27.    Sellmann C, Priebs J, Landmann M, Degen C, Engstler AJ, Jin CJ, et al. Diets rich in fructose, fat or fructose and fat alter intestinal barrier function and lead to the development of nonalcoholic fatty liver disease over time. J Nutr Biochem 2015;26:1183-1192.
28.    Hussien NI, Shoman AA. Effect of obesity and passive smoking on biochemical and histopathological changes in rat Liver and the protective effect of exercise. J Exerc Physiol Online 2013;16;101-111.
29.    Ip E, Farrell GC, Robertson G, Hall P, Kirsch R, Leclercq I. Central role of PPARalpha-dependent hepatic lipid turnover in dietary steatohepatitis in mice. J Hepatol 2003;38:123-132.
30.    Bruck R, Aeed H, Avni Y, Shirin H, Matas Z, Shahmurov M, et al. Melatonin inhibits nuclear factor kappa B activation and oxidativestress and protects against thioacetamide induced liver damage in rats. J Hepato2003;40:86-93.
31.    Araujo JA. Particulate air pollution, systemic oxidative stress, inflammation, and atherosclerosis. Air Qual Atmos Health 2010;4:79-93.
32.    Hyder O, Chung M, Cosgrove D, Herman JM, Li Z, Firoozmand A, et al. Cadmium exposure and liver disease among US adults. J Gastrointest Surg 2013;17:1265-1273.
33.    VoPham T. Environmental risk factors for liver cancer and nonalcoholic fatty liver disease. Curr Epidemiol Rep 2019;6:50-66.
34.    Cave M, Appana S, Patel M, Falkner KC, McClain CJ, Brock G. Polychlorinated biphenyls, lead, and mercury are associated with liver disease in American adults: NHANES 2003-2004. Environ Health Perspect 2010;118:1735-1742.
35.    Hsu C-L, Yen G-C. Effect of gallic acid on high fat diet-induced dyslipidaemia, hepatosteatosis and oxidative stress in rats. Br J Nutr 2007;98: 27-35.
36.    Ayres JG, Borm P, Cassee FR, Castranova V, Donaldson K, Ghio A, et al. Evaluating the toxicity of airborne particulate matter and nanoparticles by measuring oxidative stress potential—a workshop report and consensus statement. Inhal Toxicol 2008;20:75-99.
37.    Bayramoglu G, Kurt H, Bayramoglu A, Gunes HV, Degirmenci İ, Colak S. Preventive role of gallic acid on hepatic ischemia and reperfusion injury in rats. Cytotechnology 2015;67:845-849.
38.    Andand K, Sinch B, Saxena AK, Chandan BK, Gupta VN, Bhardwaj V. 3,4,5-trihydroxy benzoic acid   gallic acid, the hepato protective principle in the fruits of terminaliabelerica-bioassay guided activity. Pharmacolo Res 1997; 36:315-321.
39.    Jalili C, Tabatabaei H, Kakaberiei S, Roshankhah S, Salahshoor MR. Protective role of crocin against nicotine-induced damages on male mice liver. Int  J Pre Med 2015;6:92-104.
40.    Xu X, Yavar Z, Verdin M, Ying Z, Mihai G, Kampfrath T, et al. Effect of early particulate air pollution exposure on obesity in mice role of p47phox. Arterioscl Thorom Vas J 2010;30:2518-2527.
41.    Sun Q, Yue P, Deiuliis JA, Lumeng CN, Kampfrath T, Mikolaj MB, et al. Ambient air pollution exaggerates adipose inflammation and insulin resistance in a mouse model of diet-induced obesity. Circulation 2009;119:538-5346.
42.    Je J-Y, Lee D-B. Nelumbo nucifera leaves protect hydrogen peroxide-induced hepatic damage via anti-oxidant enzymes and HO-1/Nrf2 activation. Food Funct 2015;6:1911-1918.
43.    Sivandzade F, Prasad S, Bhalerao A, Cucullo L. NRF2 and NF-B interplay in cerebrovascular and neurodegenerative disorders: Molecular mechanisms and possible therapeutic approaches. Redox Biol 2019;21:101059.
44.    Vignal C, Pichavant M, Alleman LY, Djouina M, Dingreville F, Perdrix E, et al. Effects of urban coarse particles inhalation on oxidative and inflammatory parameters in the mouse lung and colon. Part Fibre Toxicol 2017;14:46-59.
45.    Shanmuganathan S, Angayarkanni N. Chebulagic acid chebulinic acid and gallic acid, the active principles of Triphala, inhibit TNFα induced pro-angiogenic and pro-inflammatory activities in retinal capillary endothelial cells by inhibiting p38, ERK and NFkB phosphorylation. Vascul pharmacol 2018;108:23-35.
46.    Liu X, Meng Z. Effects of airborne fine particulate matter on anti-oxidant capacity and lipid peroxidation in multiple organs of rats. Inhal Toxicol 2005;17:467-473.
47.    Ahmadvand H, Babaeenezhad E, Moradi FH, Venool AC. Effect of gallic acid on liver oxidative stress markers in renal ischemia-reperfusion injury in rats. Ann Res Antioxid 2017; 2: e03.