Targeted metabolomics reveals the therapeutic impact of Eclipta prostrata on diet-induced non-alcoholic fatty liver disease in rats

Azza S. Helmy; Naglaa M. Sherif; Hassan Z. Ghanem; Nabaweya A. Ibrahim; Abdel Nasser G. El Gendy; Noha S. Hussein; Abdel-Hamid Z. Abdel-Hamid

doi:10.7324/JAPS.2019.S109

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Abstract

Non-alcoholic fatty liver disease (NAFLD) is a growing clinical problem worldwide. The current study aimed to evaluate the therapeutic effect of the methanol extract of Eclipta prostrata (E. prostrata) in rats using gas chromatography–mass spectrometry (GC–MS) followed by multivariate and univariate data analysis. Phytochemical study of E. prostrata extract was performed using chemical, colorimetric, and high-performance liquid chromatography (HPLC) analysis. Forty-two Wistar albino rats divided into seven groups (six in each) were used in this study. Fatty liver was induced in rats using a high-fat diet together with cholesterol and cholic acid, then they were treated with different doses of E. prostrata. The histopathological examination of liver and NAFLD activity score showed significant markers for the diagnosis of the early stage of the disease. Treatment with high doses of E. prostrata (300 and 200 mg/kg BW) extract exhibited significant improvement in liver function and lipid profile in rats bearing NAFLD. Lipidomic analysis showed a discrete variability in the levels of some metabolites, including cholest-5-en-3-ol (3β) – acetate; cholesta-4, 6-dien-3-ol, (3β); urea; 1,3 dipalmitin; glycerol; linoleic acid; and arachidonic acid in sera of rats bearing NAFLD in contrast to healthy ones. Treatment with E. prostrata extract showed noticeable amelioration in the levels of these metabolites. The present results concluded that E. prostrata in high doses (300 and 200 mg/kg BW) had the potential efficacy to ameliorate NAFLD. Nevertheless, lipidomics could be used for the early detection of NAFLD and in the assessment of the mechanism of herbal medications.

Keyword: Eclipta prostrata GC–MS Lipidomics NAFLD.

Citation:

Helmy AS, Sherif NM, Ghanem HZ, Ibrahim NA, El Gendy AG, Hussein NS, Abdel-Hamid AZ. Targeted metabolomics reveals the therapeutic impact of Eclipta prostrata on diet-induced non-alcoholic fatty liver disease in rats. J Appl Pharm Sci, 2019; 9(S1):077–090.

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Reference

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Ammar NM, Farag MA, Kholeif TE, Metwally NS, El-Sheikh NM, El Gendy AN, Abdel-Hamid AH. Serum metabolomics reveals the mechanistic role of functional foods and exercise for obesity management in rats. J Pharm Biomed Anal, 2017; 142:91–101. https://doi.org/10.1016/j.jpba.2017.05.001
Arun K, Balasubramanian U. Comparative study on Hepatoprotective activity of Aegle marmelos and Eclipta alba against alcohol induced in albino rats. Int J Environ Sci, 2011; 2:401–14.
Banso A, Adeyemo S. Phytochemical screening and antimicrobial assessment of Abutilon mauritianum, Bacopa monnifera and Datura stramonium. Biokemistri, 2006; 18:39–44.
Bellentani S, Tiribelli C, Saccoccio G, Sodde M, Fratti N, De Martin C, Christianini G. Prevalence of chronic liver disease in the general population of northern Italy: the Dionysos Study. Hepatology, 1994; 20:1442–9. https://doi.org/10.1002/hep.1840200611
Bergmeyer HU, Bowers GNJ, Horder M, Moss DW. Provisional recommendations on IFCC methods for the measurement of catalytic concentrations of enzymes. Part 2. IFCC method for aspartate aminotransferase. Clin Chim Acta, 1976; 70:F19–29. https://doi.org/10.1016/0009-8981(76)90437-X
Bhardwaj S, Gupta D. Study of acute, Subacute and chronic toxicity test. Int J Adv Res Pharm Bio Sci, 2012; 1:103–129.
Bravo E, Palleschi S, Aspichueta P, Buqué X, Rossi B, Cano A, Napolitano M, Ochoa B, Botham KM. High fat diet-induced non alcoholic fatty liver disease in rats is associated with hyperhomocysteinemia caused by down regulation of the transsulphuration pathway. Lipids Health Dis, 2011; 10:60. https://doi.org/10.1186/1476-511X-10-60
Castelli WP, Doyle JT, Gordon T, Hames CG, Hjortland MC, Hulley SB, Kagan A, Zukel WJ. HDL cholesterol and other lipids in coronary heart disease. The cooperative lipoprotein phenotyping study. Circulation, 1977; 55:767–72. https://doi.org/10.1161/01.CIR.55.5.767
Chao J, Huo T-I, Cheng H-Y, Tsai JC, Liao JW, Lee MS, Qin XM, Hsieh MT, Pao LH, Peng WH. Gallic acid ameliorated impaired glucose and lipid homeostasis in high fat diet-induced NAFLD mice. PLoS One, 2014; 9:e96969. https://doi.org/10.1371/journal.pone.0096969
Dhandapani R. Hypolipidemic activity of Eclipta prostrata (L.) L. leaf extract in atherogenic diet induced hyperlipidemic rats. Indian J Exp Biol, 2007; 45:617–9.
Diraison F, Moulin P, Beylot M. Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease. Diabetes Metab, 2003; 29:478–85. https://doi.org/10.1016/S1262-3636(07)70061-7
Fakurazi S, Hairuszah I, Nanthini U. Moringa oleifera Lam prevents acetaminophen induced liver injury through restoration of glutathione level. Food Chem Toxicol, 2008; 46:2611–5. https://doi.org/10.1016/j.fct.2008.04.018
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Kim D-O, Chun OK, Kim YJ, Moon H-Y, Lee CY. Quantification of polyphenolics and their antioxidant capacity in fresh plums. J Agric Food Chem, 2003; 51:6509–15. https://doi.org/10.1021/jf0343074
Kozarsky KF, Donahee MH, Rigotti A, Iqbal SN, Edelman ER, Krieger M. Overexpression of the HDL receptor SR-BI alters plasma HDL and bile cholesterol levels. Nature, 1997; 387:414–7. https://doi.org/10.1038/387414a0
Kuivenhoven JA, Jukema JW, Zwinderman AH, de Knijff P, McPherson R, Bruschke AV, Lie KI, Kastelein JJ. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group. N Engl J Med, 1998; 338:86–93. https://doi.org/10.1056/NEJM199801083380203
Kumari CS, Govindasamy S, Sukumar E. Lipid lowering activity of Eclipta prostrata in experimental hyperlipidemia. J Ethnopharmacol, 2006; 105:332–5. https://doi.org/10.1016/j.jep.2005.10.031
Liu Z-Q, Shan H-Y. Cholesterol, not polyunsaturated fatty acids, is target molecule in oxidation induced by reactive oxygen species in membrane of human erythrocytes. Cell Biochem Biophys, 2006; 45:185–93. https://doi.org/10.1385/CBB:45:2:185
Maciejewska D, Ossowski P, Drozd A, Ryterska K, JamioÅ‚-Milc D, Banaszczak M, Kaczorowska M, Sabinicz A, Raszeja-Wyszomirska J, Stachowska E. Metabolites of arachidonic acid and linoleic acid in early stages of non-alcoholic fatty liver disease—a pilot study. Prostaglandins Other Lipid Mediat, 2015; 121:184–9. https://doi.org/10.1016/j.prostaglandins.2015.09.003
Matyash V, Liebisch G, Kurzchalia TV, Shevchenko A, Schwudke D. Lipid extraction by methyl-tert-butyl ether for high-throughput lipidomics. J Lipid Res, 2008; 49:1137–46. https://doi.org/10.1194/jlr.D700041-JLR200
Mroczek A, Kapusta I, Janda B, Janiszowska W. Triterpene saponin content in the roots of red beet (Beta vulgaris L.) cultivars. J Agric Food Chem, 2012; 60:12397–402. https://doi.org/10.1021/jf303952x
Mushtaq S, Abbasi BH, Uzair B, Abbasi R. Natural products as reservoirs of novel therapeutic agents. EXCLI J, 2018; 17:420–51.
Ney DM, Lasekan JB, Shinnick FL. Soluble oat fiber tends to normalize lipoprotein composition in cholesterol-fed rats. J Nutr, 1988; 118:1455–62. https://doi.org/10.1093/jn/118.12.1455
Porras D, Nistal E. Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related. Free Radic Biol, 2017; 102:188–202. https://doi.org/10.1016/j.freeradbiomed.2016.11.037
Prabu K, Kanchana N, Sadiq AM. Hepatoprotective effect of Eclipta alba on paracetamol induced liver toxicity in rats. J Microbiol Biotechnol Res, 2011; 1:75–9.
Puri P, Baillie RA, Wiest MM, Mirshahi F, Choudhury J, Cheung O, Sargeant C, Contos MJ, Sanyal AJ. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology, 2007; 46:1081–90. https://doi.org/10.1002/hep.21763
Puri P, Wiest MM, Cheung O, Mirshahi F, Sargeant C, Min HK, Contos MJ, Sterling RK, Fuchs M, Zhou H, Watkins SM. The plasma lipidomic signature of nonalcoholic steatohepatitis. Hepatology, 2009; 50:1827–38. https://doi.org/10.1002/hep.23229
Rader DJ, Alexander ET, Weibel GL, Billheimer J, Rothblat GH. The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis. J Lipid Res, 2009; 50:S189–94. https://doi.org/10.1194/jlr.R800088-JLR200
Reeves PG, Nielsen FH, Fahey GCJ. AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. 1993; 123:1939-1951.
Reitman S, Frankel S. A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am J Clin Pathol, 1957; 28:56–63. https://doi.org/10.1093/ajcp/28.1.56
Rodriguez A, Gena P, Mendez-Gimenez L, Rosito A, Valentí V, Rotellar F, Sola I, Moncada R, Silva C, Svelto M, Salvador J. Reduced hepatic aquaporin-9 and glycerol permeability are related to insulin resistance in non-alcoholic fatty liver disease. Int J Obes (Lond), 2014; 38:1213–20. https://doi.org/10.1038/ijo.2013.234
Sanyal D, Mukherjee P, Raychaudhuri M, Ghosh S, Mukherjee S, Chowdhury S. Profile of liver enzymes in non-alcoholic fatty liver disease in patients with impaired glucose tolerance and newly detected untreated type 2 diabetes. Indian J Endocrinol Metab, 2015; 19:597–601. https://doi.org/10.4103/2230-8210.163172
Serviddio G, Bellanti F, Villani R, Tamborra R, Zerbinati C, Blonda M, Ciacciarelli M, Poli G, Vendemiale G, Iuliano L. Effects of dietary fatty acids and cholesterol excess on liver injury: a lipidomic approach. Redox Biol, 2016; 9:296–305. https://doi.org/10.1016/j.redox.2016.09.002
Singleton VL, Rossi JA. Colorimetry of total phenolics with phosphomolybdic-phosphotungstic acid reagents. Am J Enol Vitic, 1965; 16:144 LP–158.
Smith A, Bruton JW. colour atlas of histological staining techniques. J Clin Pathol, 1978; 31:289.
Straub BK, Schirmacher P. Pathology and biopsy assessment of non-alcoholic fatty liver disease. Dig Dis, 2010; 28:197–202. https://doi.org/10.1159/000282086
Sun Z-H, Zhang C, Zhang M. A new benzoic acid derivative from Eclipta prostrata. 2010; 8:244-246.
Tammela T, Enholm B, Alitalo K, Paavonen K. The biology of vascular endothelial growth factors. Cardiovasc Res, 2005; 65:550–63. https://doi.org/10.1016/j.cardiores.2004.12.002
Targher G, Chonchol M, Zoppini G, Abaterusso C, Bonora E. Risk of chronic kidney disease in patients with non-alcoholic fatty liver disease: is there a link? J Hepatol, 2011; 54:1020–9. https://doi.org/10.1016/j.jhep.2010.11.007
Wolf C, Quinn PJ. Lipidomics: practical aspects and applications. Prog Lipid Res, 2008; 47:15–36. https://doi.org/10.1016/j.plipres.2007.09.001
Wu CH, Lin MC, Wang HC, Yang MY, Jou MJ, Wang CJ. Rutin inhibits oleic acid induced lipid accumulation via reducing lipogenesis and oxidative stress in hepatocarcinoma cells. J Food Sci, 2011; 76:65–72. https://doi.org/10.1111/j.1750-3841.2010.02033.x
Xia J, Psychogios N, Young N, Wishart DS. MetaboAnalyst: a web server for metabolomic data analysis and interpretation. Nucleic Acids Res, 2009; 37:W652–60. https://doi.org/10.1093/nar/gkp356
Yuan JC, Jiang YH, Sheng ZP. Study progress on the chemical constituents of Herba ecliptae. Asia-Pacific Tradit Med, 2009; 5:125–7.
Zehethofer N, Pinto DM. Recent developments in tandem mass spectrometry for lipidomic analysis. Anal Chim Acta, 2008; 627:62–70. https://doi.org/10.1016/j.aca.2008.06.045
Zhao Y, Peng L, Yang L-C, Xu XD, Li WJ, Luo XM, Jin X. Wedelolactone regulates lipid metabolism and improves hepatic steatosis partly by AMPK activation and up-regulation of expression of PPARalpha/ LPL and LDLR. PLoS One, 2015; 10:e0132720. https://doi.org/10.1371/journal.pone.0132720

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Helmy A S [PubMed] [Google Scholar ]

Sherif N M [PubMed] [Google Scholar ]

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Abdullahi MN. Evaluation of phytochemical screening and analgesic activity of aqueous extract of the leaves of Microtrichia perotitii Dc (Asteraceae) in mice using hotplate method. Med Plant Res, 2013; 3:37–43. https://doi.org/10.5376/mpr.2013.03.0005

Ammar NM, Farag MA, Kholeif TE, Metwally NS, El-Sheikh NM, El Gendy AN, Abdel-Hamid AH. Serum metabolomics reveals the mechanistic role of functional foods and exercise for obesity management in rats. J Pharm Biomed Anal, 2017; 142:91–101. https://doi.org/10.1016/j.jpba.2017.05.001

Arun K, Balasubramanian U. Comparative study on Hepatoprotective activity of Aegle marmelos and Eclipta alba against alcohol induced in albino rats. Int J Environ Sci, 2011; 2:401–14.

Banso A, Adeyemo S. Phytochemical screening and antimicrobial assessment of Abutilon mauritianum, Bacopa monnifera and Datura stramonium. Biokemistri, 2006; 18:39–44.

Bellentani S, Tiribelli C, Saccoccio G, Sodde M, Fratti N, De Martin C, Christianini G. Prevalence of chronic liver disease in the general population of northern Italy: the Dionysos Study. Hepatology, 1994; 20:1442–9. https://doi.org/10.1002/hep.1840200611

Bergmeyer HU, Bowers GNJ, Horder M, Moss DW. Provisional recommendations on IFCC methods for the measurement of catalytic concentrations of enzymes. Part 2. IFCC method for aspartate aminotransferase. Clin Chim Acta, 1976; 70:F19–29. https://doi.org/10.1016/0009-8981(76)90437-X

Bhardwaj S, Gupta D. Study of acute, Subacute and chronic toxicity test. Int J Adv Res Pharm Bio Sci, 2012; 1:103–129.

Bravo E, Palleschi S, Aspichueta P, Buqué X, Rossi B, Cano A, Napolitano M, Ochoa B, Botham KM. High fat diet-induced non alcoholic fatty liver disease in rats is associated with hyperhomocysteinemia caused by down regulation of the transsulphuration pathway. Lipids Health Dis, 2011; 10:60. https://doi.org/10.1186/1476-511X-10-60

Castelli WP, Doyle JT, Gordon T, Hames CG, Hjortland MC, Hulley SB, Kagan A, Zukel WJ. HDL cholesterol and other lipids in coronary heart disease. The cooperative lipoprotein phenotyping study. Circulation, 1977; 55:767–72. https://doi.org/10.1161/01.CIR.55.5.767

Chao J, Huo T-I, Cheng H-Y, Tsai JC, Liao JW, Lee MS, Qin XM, Hsieh MT, Pao LH, Peng WH. Gallic acid ameliorated impaired glucose and lipid homeostasis in high fat diet-induced NAFLD mice. PLoS One, 2014; 9:e96969. https://doi.org/10.1371/journal.pone.0096969

Dhandapani R. Hypolipidemic activity of Eclipta prostrata (L.) L. leaf extract in atherogenic diet induced hyperlipidemic rats. Indian J Exp Biol, 2007; 45:617–9.

Diraison F, Moulin P, Beylot M. Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease. Diabetes Metab, 2003; 29:478–85. https://doi.org/10.1016/S1262-3636(07)70061-7

Fakurazi S, Hairuszah I, Nanthini U. Moringa oleifera Lam prevents acetaminophen induced liver injury through restoration of glutathione level. Food Chem Toxicol, 2008; 46:2611–5. https://doi.org/10.1016/j.fct.2008.04.018

Fossati P, Prencipe L. Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem, 1982; 28:2077–80.

Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem, 1972; 18:499–502.

Gorden DL, Myers DS, Ivanova PT, Fahy E, Maurya MR, Gupta S, Min J, Spann NJ, McDonald JG, Kelly SL, Duan J. Biomarkers of NAFLD progression: a lipidomics approach to an epidemic. J Lipid Res, 2015; 56:722–36. https://doi.org/10.1194/jlr.P056002

Haga Y, Kanda T, Sasaki R, Nakamura M, Nakamoto S, Yokosuka O. Nonalcoholic fatty liver disease and hepatic cirrhosis: comparison with viral hepatitis-associated steatosis. World J Gastroenterol, 2015; 21:12989–95. https://doi.org/10.3748/wjg.v21.i46.12989

Joshi A, Bhobe M, Sattarkar A. Phytochemical investigation of the roots of Grewia microcos Linn. J Chem Pharm Res, 2013; 5:80–7.

Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol, 2010; 8:e1000412. https://doi.org/10.1371/journal.pbio.1000412

Kim D-O, Chun OK, Kim YJ, Moon H-Y, Lee CY. Quantification of polyphenolics and their antioxidant capacity in fresh plums. J Agric Food Chem, 2003; 51:6509–15. https://doi.org/10.1021/jf0343074

Kozarsky KF, Donahee MH, Rigotti A, Iqbal SN, Edelman ER, Krieger M. Overexpression of the HDL receptor SR-BI alters plasma HDL and bile cholesterol levels. Nature, 1997; 387:414–7. https://doi.org/10.1038/387414a0

Kuivenhoven JA, Jukema JW, Zwinderman AH, de Knijff P, McPherson R, Bruschke AV, Lie KI, Kastelein JJ. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group. N Engl J Med, 1998; 338:86–93. https://doi.org/10.1056/NEJM199801083380203

Kumari CS, Govindasamy S, Sukumar E. Lipid lowering activity of Eclipta prostrata in experimental hyperlipidemia. J Ethnopharmacol, 2006; 105:332–5. https://doi.org/10.1016/j.jep.2005.10.031

Liu Z-Q, Shan H-Y. Cholesterol, not polyunsaturated fatty acids, is target molecule in oxidation induced by reactive oxygen species in membrane of human erythrocytes. Cell Biochem Biophys, 2006; 45:185–93. https://doi.org/10.1385/CBB:45:2:185

Maciejewska D, Ossowski P, Drozd A, Ryterska K, JamioÅ‚-Milc D, Banaszczak M, Kaczorowska M, Sabinicz A, Raszeja-Wyszomirska J, Stachowska E. Metabolites of arachidonic acid and linoleic acid in early stages of non-alcoholic fatty liver disease—a pilot study. Prostaglandins Other Lipid Mediat, 2015; 121:184–9. https://doi.org/10.1016/j.prostaglandins.2015.09.003

Matyash V, Liebisch G, Kurzchalia TV, Shevchenko A, Schwudke D. Lipid extraction by methyl-tert-butyl ether for high-throughput lipidomics. J Lipid Res, 2008; 49:1137–46. https://doi.org/10.1194/jlr.D700041-JLR200

Mroczek A, Kapusta I, Janda B, Janiszowska W. Triterpene saponin content in the roots of red beet (Beta vulgaris L.) cultivars. J Agric Food Chem, 2012; 60:12397–402. https://doi.org/10.1021/jf303952x

Mushtaq S, Abbasi BH, Uzair B, Abbasi R. Natural products as reservoirs of novel therapeutic agents. EXCLI J, 2018; 17:420–51.

Ney DM, Lasekan JB, Shinnick FL. Soluble oat fiber tends to normalize lipoprotein composition in cholesterol-fed rats. J Nutr, 1988; 118:1455–62. https://doi.org/10.1093/jn/118.12.1455

Porras D, Nistal E. Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related. Free Radic Biol, 2017; 102:188–202. https://doi.org/10.1016/j.freeradbiomed.2016.11.037

Prabu K, Kanchana N, Sadiq AM. Hepatoprotective effect of Eclipta alba on paracetamol induced liver toxicity in rats. J Microbiol Biotechnol Res, 2011; 1:75–9.

Puri P, Baillie RA, Wiest MM, Mirshahi F, Choudhury J, Cheung O, Sargeant C, Contos MJ, Sanyal AJ. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology, 2007; 46:1081–90. https://doi.org/10.1002/hep.21763

Puri P, Wiest MM, Cheung O, Mirshahi F, Sargeant C, Min HK, Contos MJ, Sterling RK, Fuchs M, Zhou H, Watkins SM. The plasma lipidomic signature of nonalcoholic steatohepatitis. Hepatology, 2009; 50:1827–38. https://doi.org/10.1002/hep.23229

Rader DJ, Alexander ET, Weibel GL, Billheimer J, Rothblat GH. The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis. J Lipid Res, 2009; 50:S189–94. https://doi.org/10.1194/jlr.R800088-JLR200

Reeves PG, Nielsen FH, Fahey GCJ. AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. 1993; 123:1939-1951.

Reitman S, Frankel S. A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am J Clin Pathol, 1957; 28:56–63. https://doi.org/10.1093/ajcp/28.1.56

Rodriguez A, Gena P, Mendez-Gimenez L, Rosito A, Valentí V, Rotellar F, Sola I, Moncada R, Silva C, Svelto M, Salvador J. Reduced hepatic aquaporin-9 and glycerol permeability are related to insulin resistance in non-alcoholic fatty liver disease. Int J Obes (Lond), 2014; 38:1213–20. https://doi.org/10.1038/ijo.2013.234

Sanyal D, Mukherjee P, Raychaudhuri M, Ghosh S, Mukherjee S, Chowdhury S. Profile of liver enzymes in non-alcoholic fatty liver disease in patients with impaired glucose tolerance and newly detected untreated type 2 diabetes. Indian J Endocrinol Metab, 2015; 19:597–601. https://doi.org/10.4103/2230-8210.163172

Serviddio G, Bellanti F, Villani R, Tamborra R, Zerbinati C, Blonda M, Ciacciarelli M, Poli G, Vendemiale G, Iuliano L. Effects of dietary fatty acids and cholesterol excess on liver injury: a lipidomic approach. Redox Biol, 2016; 9:296–305. https://doi.org/10.1016/j.redox.2016.09.002

Singleton VL, Rossi JA. Colorimetry of total phenolics with phosphomolybdic-phosphotungstic acid reagents. Am J Enol Vitic, 1965; 16:144 LP–158.

Smith A, Bruton JW. colour atlas of histological staining techniques. J Clin Pathol, 1978; 31:289.

Straub BK, Schirmacher P. Pathology and biopsy assessment of non-alcoholic fatty liver disease. Dig Dis, 2010; 28:197–202. https://doi.org/10.1159/000282086

Sun Z-H, Zhang C, Zhang M. A new benzoic acid derivative from Eclipta prostrata. 2010; 8:244-246.

Tammela T, Enholm B, Alitalo K, Paavonen K. The biology of vascular endothelial growth factors. Cardiovasc Res, 2005; 65:550–63. https://doi.org/10.1016/j.cardiores.2004.12.002

Targher G, Chonchol M, Zoppini G, Abaterusso C, Bonora E. Risk of chronic kidney disease in patients with non-alcoholic fatty liver disease: is there a link? J Hepatol, 2011; 54:1020–9. https://doi.org/10.1016/j.jhep.2010.11.007

Wolf C, Quinn PJ. Lipidomics: practical aspects and applications. Prog Lipid Res, 2008; 47:15–36. https://doi.org/10.1016/j.plipres.2007.09.001

Wu CH, Lin MC, Wang HC, Yang MY, Jou MJ, Wang CJ. Rutin inhibits oleic acid induced lipid accumulation via reducing lipogenesis and oxidative stress in hepatocarcinoma cells. J Food Sci, 2011; 76:65–72. https://doi.org/10.1111/j.1750-3841.2010.02033.x

Xia J, Psychogios N, Young N, Wishart DS. MetaboAnalyst: a web server for metabolomic data analysis and interpretation. Nucleic Acids Res, 2009; 37:W652–60. https://doi.org/10.1093/nar/gkp356

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Zehethofer N, Pinto DM. Recent developments in tandem mass spectrometry for lipidomic analysis. Anal Chim Acta, 2008; 627:62–70. https://doi.org/10.1016/j.aca.2008.06.045

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