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Combinatorial Chemistry & High Throughput Screening

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ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Research Article

Liver Metabolomics Analysis Revealing Key Metabolites Associated with Different Stages of Nonalcoholic Fatty Liver Disease in Hamsters

Author(s): Shan-Shan Gao, Yue-Liang Shen, Yun-Wen Chen, Xiu-Zhi Wei, Jing-Jing Hu, Jue Wang and Wen-Jing Wu*

Volume 27, Issue 9, 2024

Published on: 04 October, 2023

Page: [1303 - 1317] Pages: 15

DOI: 10.2174/0113862073238503230924180432

Price: $65

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Abstract

Background and Aim: Nonalcoholic fatty liver disease (NAFLD) is not only the top cause of liver diseases but also a hepatic-correlated metabolic syndrome. This study performed untargeted metabolomics analysis of NAFLD hamsters to identify the key metabolites to discriminate different stages of NAFLD.

Methods: Hamsters were fed a high-fat diet (HFD) to establish the NAFLD model with different stages (six weeks named as the NAFLD1 group and twelve weeks as the NAFLD2 group, respectively). Those liver samples were analyzed by untargeted metabolomics (UM) analysis to investigate metabolic changes and metabolites to discriminate different stages of NAFLD.

Results: The significant liver weight gain in NAFLD hamsters was observed, accompanied by significantly increased levels of serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Moreover, the levels of TG, LDL-C, ALT, and AST were significantly higher in the NAFLD2 group than in the NAFLD1 group. The UM analysis also revealed the metabolic changes; 27 differently expressed metabolites were detected between the NAFLD2 and NAFLD1 groups. More importantly, the levels of N-methylalanine, allantoin, glucose, and glutamylvaline were found to be significantly different between any two groups (control, NAFLD2 and NAFLD1). Receiver operating characteristic curve (ROC) curve results also showed that these four metabolites are able to distinguish control, NAFLD1 and NAFLD2 groups.

Conclusion: This study indicated that the process of NAFLD in hamsters is accompanied by different metabolite changes, and these key differently expressed metabolites may be valuable diagnostic biomarkers and responses to therapeutic interventions.

Graphical Abstract

[1]
Paul, S.; Davis, A.M. Diagnosis and management of nonalcoholic fatty liver disease. JAMA, 2018, 320(23), 2474-2475.
[http://dx.doi.org/10.1001/jama.2018.17365] [PMID: 30476962]
[2]
Diehl, A.M.; Day, C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N. Engl. J. Med., 2017, 377(21), 2063-2072.
[http://dx.doi.org/10.1056/NEJMra1503519] [PMID: 29166236]
[3]
Nobili, V.; Alisi, A.; Valenti, L.; Miele, L.; Feldstein, A.E.; Alkhouri, N. NAFLD in children: New genes, new diagnostic modalities and new drugs. Nat. Rev. Gastroenterol. Hepatol., 2019, 16(9), 517-530.
[http://dx.doi.org/10.1038/s41575-019-0169-z] [PMID: 31278377]
[4]
Younossi, Z.M.; Otgonsuren, M.; Henry, L.; Venkatesan, C.; Mishra, A.; Erario, M.; Hunt, S. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology, 2015, 62(6), 1723-1730.
[http://dx.doi.org/10.1002/hep.28123] [PMID: 26274335]
[5]
Pais, R.; Barritt, A.S., IV; Calmus, Y.; Scatton, O.; Runge, T.; Lebray, P.; Poynard, T.; Ratziu, V.; Conti, F. NAFLD and liver transplantation: Current burden and expected challenges. J. Hepatol., 2016, 65(6), 1245-1257.
[http://dx.doi.org/10.1016/j.jhep.2016.07.033] [PMID: 27486010]
[6]
Hashimoto, E.; Taniai, M.; Tokushige, K. Characteristics and diagnosis of NAFLD/NASH. J. Gastroenterol. Hepatol., 2013, 28(Suppl. 4), 64-70.
[http://dx.doi.org/10.1111/jgh.12271] [PMID: 24251707]
[7]
Treeprasertsuk, S.; Björnsson, E.; Enders, F.; Suwanwalaikorn, S.; Lindor, K.D. NAFLD fibrosis score: A prognostic predictor for mortality and liver complications among NAFLD patients. World J. Gastroenterol., 2013, 19(8), 1219-1229.
[http://dx.doi.org/10.3748/wjg.v19.i8.1219] [PMID: 23482703]
[8]
Ekstedt, M.; Hagström, H.; Nasr, P.; Fredrikson, M.; Stål, P.; Kechagias, S.; Hultcrantz, R. Fibrosis stage is the strongest predictor for disease‐specific mortality in NAFLD after up to 33 years of follow‐up. Hepatology, 2015, 61(5), 1547-1554.
[http://dx.doi.org/10.1002/hep.27368] [PMID: 25125077]
[9]
Wishart, D.S. Emerging applications of metabolomics in drug discovery and precision medicine. Nat. Rev. Drug Discov., 2016, 15(7), 473-484.
[http://dx.doi.org/10.1038/nrd.2016.32] [PMID: 26965202]
[10]
Chen, G. The link between hepatic vitamin A metabolism and nonalcoholic fatty liver disease. Curr. Drug Targets, 2015, 16(12), 1281-1292.
[http://dx.doi.org/10.2174/1389450116666150325231015] [PMID: 25808650]
[11]
Wang, G.E.; Li, Y.F.; Zhai, Y.J.; Gong, L.; Tian, J.Y.; Hong, M.; Yao, N.; Wu, Y.P.; Kurihara, H.; He, R.R. Theacrine protects against nonalcoholic fatty liver disease by regulating acylcarnitine metabolism. Metabolism, 2018, 85, 227-239.
[http://dx.doi.org/10.1016/j.metabol.2018.04.011] [PMID: 29727630]
[12]
Onorato, A.; Fiore, E.; Bayo, J.; Casali, C.; Fernandez-Tomé, M.; Rodríguez, M.; Domínguez, L.; Argemi, J.; Hidalgo, F.; Favre, C.; García, M.; Atorrasagasti, C.; Mazzolini, G.D. SPARC inhibition accelerates NAFLD‐associated hepatocellular carcinoma development by dysregulating hepatic lipid metabolism. Liver Int., 2021, 41(7), 1677-1693.
[http://dx.doi.org/10.1111/liv.14857] [PMID: 33641248]
[13]
Elbadawy, M.; Yamanaka, M.; Goto, Y.; Hayashi, K.; Tsunedomi, R.; Hazama, S.; Nagano, H.; Yoshida, T.; Shibutani, M.; Ichikawa, R.; Nakahara, J.; Omatsu, T.; Mizutani, T.; Katayama, Y.; Shinohara, Y.; Abugomaa, A.; Kaneda, M.; Yamawaki, H.; Usui, T.; Sasaki, K. Efficacy of primary liver organoid culture from different stages of non-alcoholic steatohepatitis (NASH) mouse model. Biomaterials, 2020, 237, 119823.
[http://dx.doi.org/10.1016/j.biomaterials.2020.119823] [PMID: 32044522]
[14]
Han, L.; Zhao, L.H.; Zhang, M.L.; Li, H.T.; Gao, Z.Z.; Zheng, X.J.; Wang, X.M.; Wu, H.R.; Zheng, Y.J.; Jiang, X.T.; Ding, Q.Y.; Yang, H.Y.; Jia, W.P.; Tong, X.L. A novel antidiabetic monomers combination alleviates insulin resistance through bacteria-cometabolism-inflammation responses. Front. Microbiol., 2020, 11, 173.
[http://dx.doi.org/10.3389/fmicb.2020.00173] [PMID: 32132984]
[15]
Estes, C.; Anstee, Q.M.; Arias-Loste, M.T.; Bantel, H.; Bellentani, S.; Caballeria, J.; Colombo, M.; Craxi, A.; Crespo, J.; Day, C.P.; Eguchi, Y.; Geier, A.; Kondili, L.A.; Kroy, D.C.; Lazarus, J.V.; Loomba, R.; Manns, M.P.; Marchesini, G.; Nakajima, A.; Negro, F.; Petta, S.; Ratziu, V.; Romero-Gomez, M.; Sanyal, A.; Schattenberg, J.M.; Tacke, F.; Tanaka, J.; Trautwein, C.; Wei, L.; Zeuzem, S.; Razavi, H. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030. J. Hepatol., 2018, 69(4), 896-904.
[http://dx.doi.org/10.1016/j.jhep.2018.05.036] [PMID: 29886156]
[16]
Estes, C.; Razavi, H.; Loomba, R.; Younossi, Z.; Sanyal, A.J. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology, 2018, 67(1), 123-133.
[http://dx.doi.org/10.1002/hep.29466] [PMID: 28802062]
[17]
Carreres, L.; Jílková, Z.M.; vial, G.; Marche, P.N.; Decaens, T.; Lerat, H. Modeling diet-induced NAFLD and NASH in rats: A comprehensive review. Biomedicines, 2021, 9(4), 378.
[http://dx.doi.org/10.3390/biomedicines9040378] [PMID: 33918467]
[18]
Maciejewska, D.; Łukomska, A.; Dec, K.; Skonieczna-Żydecka, K.; Gutowska, I.; Skórka-Majewicz, M.; Styburski, D.; Misiakiewicz-Has, K.; Pilutin, A.; Palma, J.; Sieletycka, K.; Marlicz, W.; Stachowska, E. Diet-induced rat model of gradual development of Non-Alcoholic Fatty Liver Disease (NAFLD) with Lipopolysaccharides (LPS) secretion. Diagnostics, 2019, 9(4), 205.
[http://dx.doi.org/10.3390/diagnostics9040205] [PMID: 31783667]
[19]
Gauthier, M.S.; Favier, R.; Lavoie, J.M. Time course of the development of non-alcoholic hepatic steatosis in response to high-fat diet-induced obesity in rats. Br. J. Nutr., 2006, 95(2), 273-281.
[http://dx.doi.org/10.1079/BJN20051635] [PMID: 16469142]
[20]
Sookoian, S.; Pirola, C.J. Alanine and aspartate aminotransferase and glutamine-cycling pathway: Their roles in pathogenesis of metabolic syndrome. World J. Gastroenterol., 2012, 18(29), 3775-3781.
[http://dx.doi.org/10.3748/wjg.v18.i29.3775] [PMID: 22876026]
[21]
De Chiara, F.; Heebøll, S.; Marrone, G.; Montoliu, C.; Hamilton-Dutoit, S.; Ferrandez, A.; Andreola, F.; Rombouts, K.; Grønbæk, H.; Felipo, V.; Gracia-Sancho, J.; Mookerjee, R.P.; Vilstrup, H.; Jalan, R.; Thomsen, K.L. Urea cycle dysregulation in non-alcoholic fatty liver disease. J. Hepatol., 2018, 69(4), 905-915.
[http://dx.doi.org/10.1016/j.jhep.2018.06.023] [PMID: 29981428]
[22]
Mashek, D.G.; Coleman, R.A. Cellular fatty acid uptake: The contribution of metabolism. Curr. Opin. Lipidol., 2006, 17(3), 274-278.
[http://dx.doi.org/10.1097/01.mol.0000226119.20307.2b] [PMID: 16680032]
[23]
Mashek, D.G. Hepatic lipid droplets: A balancing act between energy storage and metabolic dysfunction in NAFLD. Mol. Metab., 2021, 50, 101115.
[http://dx.doi.org/10.1016/j.molmet.2020.101115] [PMID: 33186758]
[24]
Nascimento-Ferreira, M.V.; Rendo-Urteaga, T.; Vilanova-Campelo, R.C.; Carvalho, H.B.; da Paz Oliveira, G.; Paes Landim, M.B.; Torres-Leal, F.L. The lipid accumulation product is a powerful tool to predict metabolic syndrome in undiagnosed Brazilian adults. Clin. Nutr., 2017, 36(6), 1693-1700.
[http://dx.doi.org/10.1016/j.clnu.2016.12.020] [PMID: 28081980]
[25]
Motamed, N.; Razmjou, S.; Hemmasi, G.; Maadi, M.; Zamani, F. Lipid accumulation product and metabolic syndrome: A population-based study in northern Iran, Amol. J. Endocrinol. Invest., 2016, 39(4), 375-382.
[http://dx.doi.org/10.1007/s40618-015-0369-5] [PMID: 26319991]
[26]
Nita, C.; Rusu, A.; Hancu, N.; Roman, G.; Bala, C. Hypertensive waist and lipid accumulation product as predictors of metabolic syndrome. Metab. Syndr. Relat. Disord., 2018, 16(10), 505-506.
[http://dx.doi.org/10.1089/met.2018.0098] [PMID: 30300092]
[27]
Agius, L. Dietary carbohydrate and control of hepatic gene expression: Mechanistic links from ATP and phosphate ester homeostasis to the carbohydrate-response element-binding protein. Proc. Nutr. Soc., 2016, 75(1), 10-18.
[http://dx.doi.org/10.1017/S0029665115002451] [PMID: 26264689]
[28]
Félix, D.R.; Costenaro, F.; Gottschall, C.B.A.; Coral, G.P. Non-alcoholic fatty liver disease (Nafld) in obese children- effect of refined carbohydrates in diet. BMC Pediatr., 2016, 16(1), 187.
[http://dx.doi.org/10.1186/s12887-016-0726-3] [PMID: 27846831]
[29]
Pompili, S.; Vetuschi, A.; Gaudio, E.; Tessitore, A.; Capelli, R.; Alesse, E.; Latella, G.; Sferra, R.; Onori, P. Long-term abuse of a high-carbohydrate diet is as harmful as a high-fat diet for development and progression of liver injury in a mouse model of NAFLD/NASH. Nutrition, 2020, 75-76, 110782.
[http://dx.doi.org/10.1016/j.nut.2020.110782] [PMID: 32268264]
[30]
López-Bautista, F.; Barbero-Becerra, V.J.; Ríos, M.Y.; Ramírez-Cisneros, M.Á.; Sánchez-Pérez, C.A.; Ramos-Ostos, M.H.; Uribe, M.; Chávez-Tapia, N.C.; Juárez-Hernández, E. Dietary consumption and serum pattern of bioactive fatty acids in NAFLD patients. Ann. Hepatol., 2020, 19(5), 482-488.
[http://dx.doi.org/10.1016/j.aohep.2020.06.008] [PMID: 32717363]
[31]
Balaban, S.; Lee, L.S.; Schreuder, M.; Hoy, A.J. Obesity and cancer progression: Is there a role of fatty acid metabolism? BioMed Res. Int., 2015, 2015, 1-17.
[http://dx.doi.org/10.1155/2015/274585] [PMID: 25866768]
[32]
Yamada, K.; Mizukoshi, E.; Sunagozaka, H.; Arai, K.; Yamashita, T.; Takeshita, Y.; Misu, H.; Takamura, T.; Kitamura, S.; Zen, Y.; Nakanuma, Y.; Honda, M.; Kaneko, S. Characteristics of hepatic fatty acid compositions in patients with nonalcoholic steatohepatitis. Liver Int., 2015, 35(2), 582-590.
[http://dx.doi.org/10.1111/liv.12685] [PMID: 25219574]
[33]
Sitarek, K.; Gromadzińska, J.; Stetkiewicz, J.; Lutz, P.; Król, M.; Domeradzka-Gajda, K.; Wąsowicz, W. Developmental toxicity of N-methylaniline following prenatal oral administration in rats. Int. J. Occup. Med. Environ. Health, 2016, 29(3), 479-492.
[http://dx.doi.org/10.13075/ijomeh.1896.00571] [PMID: 26988886]
[34]
Ma, J.; Meng, X.; Liu, Y.; Yin, C.; Zhang, T.; Wang, P.; Park, Y.K.; Jung, H.W. Effects of a rhizome aqueous extract of Dioscorea batatas and its bioactive compound, allantoin in high fat diet and streptozotocin-induced diabetic mice and the regulation of liver, pancreas and skeletal muscle dysfunction. J. Ethnopharmacol., 2020, 259, 112926.
[http://dx.doi.org/10.1016/j.jep.2020.112926] [PMID: 32380247]
[35]
Komeili Movahhed, T.; Moslehi, A.; Golchoob, M.; Ababzadeh, S. Allantoin improves methionine-choline deficient diet-induced nonalcoholic steatohepatitis in mice through involvement in endoplasmic reticulum stress and hepatocytes apoptosis-related genes expressions. Iran. J. Basic Med. Sci., 2019, 22(7), 736-744.
[PMID: 32373294]
[36]
Jimba, S.; Nakagami, T.; Takahashi, M.; Wakamatsu, T.; Hirota, Y.; Iwamoto, Y.; Wasada, T. Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabet. Med., 2005, 22(9), 1141-1145.
[http://dx.doi.org/10.1111/j.1464-5491.2005.01582.x] [PMID: 16108839]
[37]
Ochi, T.; Kawaguchi, T.; Nakahara, T.; Ono, M.; Noguchi, S.; Koshiyama, Y.; Munekage, K.; Murakami, E.; Hiramatsu, A.; Ogasawara, M.; Hirose, A.; Mizuta, H.; Masuda, K.; Okamoto, N.; Suganuma, N.; Chayama, K.; Yamaguchi, M.; Torimura, T.; Saibara, T. Differences in characteristics of glucose intolerance between patients with NAFLD and chronic hepatitis C as determined by CGMS. Sci. Rep., 2017, 7(1), 10146.
[http://dx.doi.org/10.1038/s41598-017-09256-4] [PMID: 28860506]
[38]
Xing, L.; Zhang, H.; Majumder, K.; Zhang, W.; Mine, Y. γ-glutamylvaline prevents low-grade chronic inflammation via activation of a calcium-sensing receptor pathway in 3T3-L1Mouse adipocytes. J. Agric. Food Chem., 2019, 67(30), 8361-8369.
[http://dx.doi.org/10.1021/acs.jafc.9b02334] [PMID: 31339708]
[39]
Mishra, P.; Pandey, C.; Singh, U.; Keshri, A.; Sabaretnam, M. Selection of appropriate statistical methods for data analysis. Ann. Card. Anaesth., 2019, 22(3), 297-301.
[http://dx.doi.org/10.4103/aca.ACA_248_18] [PMID: 31274493]
[40]
Ali, Z.; Bhaskar, S.B. Basic statistical tools in research and data analysis. Indian J. Anaesth., 2016, 60(9), 662-669.
[http://dx.doi.org/10.4103/0019-5049.190623] [PMID: 27729694]

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