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Review Articles

Application of Metabolomics in Diagnosis and Treatment of Chronic Liver Diseases

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Pages 906-916 | Published online: 04 Nov 2020

References

  • Duarte, S.; Baber, J.; Fujii, T.; Coito, A. J. Matrix Metalloproteinases in Liver Injury, Repair and Fibrosis. Matrix Biol. 2015, 44–46, 147–156. DOI: 10.1016/j.matbio.2015.01.004.
  • Racanelli, V.; Rehermann, B. The Liver as an Immunological Organ. Hepatology 2006, 43, S54–S62. DOI: 10.1002/hep.21060.
  • Robinson, M. W.; Harmon, C.; O'Farrelly, C. Liver Immunology and Its Role in Inflammation and Homeostasis. Cell. Mol. Immunol. 2016, 13, 267–276. DOI: 10.1038/cmi.2016.3.
  • Wang, A. W.; Wang, Y. J.; Zahm, A. M.; Morgan, A. R.; Wangensteen, K. J.; Kaestner, K. H. The Dynamic Chromatin Architecture of the Regenerating Liver. Cell. Mol. Gastroenterol. Hepatol. 2020, 9, 121–143. DOI: 10.1016/j.jcmgh.2019.09.006.
  • Nicolas, C. T.; Wang, Y. J.; Nyberg, S. L. Cell Therapy in Chronic Liver Disease. Curr. Opin. Gastroenterol. 2016, 32, 189–194. DOI: 10.1097/mog.0000000000000262.
  • Setiawan, V. W.; Stram, D. O.; Porcel, J.; Lu, S. C.; Le Marchand, L.; Noureddin, M. Prevalence of Chronic Liver Disease and Cirrhosis by Underlying Cause in Understudied Ethnic Groups: The Multiethnic Cohort. Hepatology 2016, 64, 1969–1977. DOI: 10.1002/hep.28677.
  • Ismail, I. T.; Fiehn, O.; Elfert, A.; Helal, M.; Salama, I.; El-Said, H. Sugar Alcohols Have a Key Role in Pathogenesis of Chronic Liver Disease and Hepatocellular Carcinoma in Whole Blood and Liver Tissues. Cancers (Basel) 2020, 12, 484. DOI: 10.3390/cancers12020484.
  • Cabral, B. C. A.; Hoffmann, L.; Bottaro, T.; Costa, P. F.; Ramos, A. L. A.; Coelho, H. S. M.; Villela-Nogueira, C. A.; Urmenyi, T. P.; Faffe, D. S.; Silva, R. Circulating microRNAs Associated with Liver Fibrosis in Chronic Hepatitis C Patients. Biochem. Biophys. Rep. 2020, 24, 100814–100814. DOI: 10.1016/j.bbrep.2020.100814.
  • Bocca, C.; Novo, E.; Miglietta, A.; Parola, M. Angiogenesis and Fibrogenesis in Chronic Liver Diseases. Cell. Mol. Gastroenterol. Hepatol. 2015, 1, 477–488. DOI: 10.1016/j.jcmgh.2015.06.011.
  • Roehlen, N.; Crouchet, E.; Baumert, T. F. Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives. Cells 2020, 9, 875. DOI: 10.3390/cells9040875.
  • Tsuji, Y.; Namisaki, T.; Kaji, K.; Takaya, H.; Nakanishi, K.; Sato, S.; Saikawa, S.; Sawada, Y.; Kitagawa, K.; Shimozato, N.; et al. Comparison of Serum Fibrosis Biomarkers for Diagnosing Significant Liver Fibrosis in Patients with Chronic Hepatitis B. Exp. Ther. Med. 2020, 20, 985–995. DOI: 10.3892/etm.2020.8798.
  • Thapa, B. R.; Walia, A. Liver Function Tests and Their Interpretation. Indian J. Pediatr. 2007, 74, 663–671. DOI: 10.1007/s12098-007-0118-7.
  • Targher, G.; Byrne, C. D. Circulating Markers of Liver Function and Cardiovascular Disease Risk. Arterioscler. Thromb. Vasc. Biol. 2015, 35, 2290–2296. DOI: 10.1161/atvbaha.115.305235.
  • Lena, C.; Gabriel, B.; Nathanaelle, G.; Pierre-Olivier, H.; Catherine, V.; Mickael, B.; Amelie, T. Discordance between Serology and Histology for Celiac Disease in a Cohort with Coexisting Liver Disorders. J. Can. Assoc. Gastroenterol. 2020, 3, 185–193. DOI: 10.1093/jcag/gwz010.
  • Kaddurah-Daouk, R.; Kristal, B. S.; Weinshilboum, R. M. Metabolomics: A Global Biochemical Approach to Drug Response and Disease. Annu. Rev. Pharmacol. Toxicol. 2008, 48, 653–683. DOI: 10.1146/annurev.pharmtox.48.113006.094715.
  • Zhang, T.; Zhang, A.; Qiu, S.; Yang, S.; Wang, X. Current Trends and Innovations in Bioanalytical Techniques of Metabolomics. Crit. Rev. Anal. Chem. 2016, 46, 342–351. DOI: 10.1080/10408347.2015.1079475.
  • Zhang, A. H.; Sun, H.; Han, Y.; Yan, G. L.; Wang, X. J. Urinary Metabolic Biomarker and Pathway Study of Hepatitis B Virus Infected Patients Based on UPLC-MS System. PLoS One 2013, 8, 8. DOI: 10.1371/journal.pone.0064381.
  • Zhou, L. N.; Wang, Q. C.; Yin, P. Y.; Xing, W. B.; Wu, Z. M.; Chen, S. L.; Lu, X.; Zhang, Y.; Lin, X. H.; Xu, G. W. Serum Metabolomics Reveals the Deregulation of Fatty Acids Metabolism in Hepatocellular Carcinoma and Chronic Liver Diseases. Anal. Bioanal. Chem. 2012, 403, 203–213. DOI: 10.1007/s00216-012-5782-4.
  • Maher, A. D.; Zirah, S. F. M.; Holmes, E.; Nicholson, J. K. Experimental and Analytical Variation in Human Urine in 1H NMR Spectroscopy-Based Metabolic Phenotyping Studies. Anal. Chem. 2007, 79, 5204–5211. DOI: 10.1021/ac070212f.
  • Bi, H.; Guo, Z.; Jia, X.; Liu, H.; Ma, L.; Xue, L. The Key Points in the Pre-Analytical Procedures of Blood and Urine Samples in Metabolomics Studies. Metabolomics 2020, 16, 68. DOI: 10.1007/s11306-020-01666-2.
  • Lauridsen, M.; Hansen, S. H.; Jaroszewski, J. W.; Cornett, C. Human Urine as Test Material in 1H NMR-Based Metabonomics: Recommendations for Sample Preparation and Storage. Anal. Chem. 2007, 79, 1181–1186. DOI: 10.1021/ac061354x.
  • Khodadadi, M.; Pourfarzam, M. A Review of Strategies for Untargeted Urinary Metabolomic Analysis Using Gas Chromatography-Mass Spectrometry. Metabolomics 2020, 16, 66. DOI: 10.1007/s11306-020-01687-x.
  • Pinto, J.; Domingues, M. R. M.; Galhano, E.; Pita, C.; Almeida, M. d C.; Carreira, I. M.; Gil, A. M. Human Plasma Stability during Handling and Storage: Impact on NMR Metabolomics. Analyst 2014, 139, 1168–1177. DOI: 10.1039/c3an02188b.
  • Larive, C. K.; Barding, G. A.; Jr.; Dinges, M. M. NMR Spectroscopy for Metabolomics and Metabolic Profiling. Anal. Chem. 2015, 87, 133–146. DOI: 10.1021/ac504075g.
  • Bliziotis, N. G.; Engelke, U. F. H.; Aspers, R.; Engel, J.; Deinum, J.; Timmers, H.; Wevers, R. A.; Kluijtmans, L. A. J. A Comparison of High-Throughput Plasma NMR Protocols for Comparative Untargeted Metabolomics. Metabolomics 2020, 16, 64. DOI: 10.1007/s11306-020-01686-y.
  • Beale, D. J.; Pinu, F. R.; Kouremenos, K. A.; Poojary, M. M.; Narayana, V. K.; Boughton, B. A.; Kanojia, K.; Dayalan, S.; Jones, O. A. H.; Dias, D. A. Review of Recent Developments in GC-MS Approaches to Metabolomics-Based Research. Metabolomics 2018, 14, 31. DOI: 10.1007/s11306-018-1449-2.
  • Cajka, T.; Fiehn, O. Toward Merging Untargeted and Targeted Methods in Mass Spectrometry-Based Metabolomics and Lipidomics. Anal. Chem. 2016, 88, 524–545. DOI: 10.1021/acs.analchem.5b04491.
  • Li, Y.; Zhang, Z.; Liu, X.; Li, A.; Hou, Z.; Wang, Y.; Zhang, Y. A Novel Approach to the Simultaneous Extraction and Non-Targeted Analysis of the Small Molecules Metabolome and Lipidome Using 96-Well Solid Phase Extraction Plates with Column-Switching Technology. J. Chromatogr. A 2015, 1409, 277–281. DOI: 10.1016/j.chroma.2015.07.048.
  • Xia, J. G.; Psychogios, N.; Young, N.; Wishart, D. S. MetaboAnalyst: A Web Server for Metabolomic Data Analysis and Interpretation. Nucleic Acids Res. 2009, 37, W652–W660. DOI: 10.1093/nar/gkp356.
  • Jóźwik, J.; Kałużna-Czaplińska, J. Current Applications of Chromatographic Methods in the Study of Human Body Fluids for Diagnosing Disorders. Crit. Rev. Anal. Chem. 2016, 46, 1–14. DOI: 10.1080/10408347.2014.929487.
  • Nassar, A. F.; Wu, T.; Nassar, S. F.; Wisnewski, A. V. UPLC-MS for Metabolomics: A Giant Step Forward in Support of Pharmaceutical Research. Drug Discov. Today 2017, 22, 463–470. DOI: 10.1016/j.drudis.2016.11.020.
  • Gebregiworgis, T.; Powers, R. Application of NMR Metabolomics to Search for Human Disease Biomarkers. Comb. Chem. High Throughput Screen. 2012, 15, 595–610. DOI: 10.2174/138620712802650522.
  • Hendriks, M. M. W. B.; Eeuwijk, F. A. v.; Jellema, R. H.; Westerhuis, J. A.; Reijmers, T. H.; Hoefsloot, H. C. J.; Smilde, A. K. Data-Processing Strategies for Metabolomics Studies. Trends Analyt. Chem. 2011, 30, 1685–1698. DOI: 10.1016/j.trac.2011.04.019.
  • Dunn, W. B.; Broadhurst, D.; Begley, P.; Zelena, E.; Francis-McIntyre, S.; Anderson, N.; Brown, M.; Knowles, J. D.; Halsall, A.; Haselden, J. N.; et al. Procedures for Large-Scale Metabolic Profiling of Serum and Plasma Using Gas Chromatography and Liquid Chromatography Coupled to Mass Spectrometry. Nat. Protoc. 2011, 6, 1060–1083. DOI: 10.1038/nprot.2011.335.
  • Wishart, D. S. Advances in Metabolite Identification. Bioanalysis 2011, 3, 1769–1782. DOI: 10.4155/bio.11.155.
  • Wishart, D. S.; Feunang, Y. D.; Marcu, A.; Guo, A. C.; Liang, K.; Vázquez-Fresno, R.; Sajed, T.; Johnson, D.; Li, C.; Karu, N.; et al. HMDB 4.0: The Human Metabolome Database for 2018. Nucleic Acids Res. 2018, 46, D608–D617. DOI: 10.1093/nar/gkx1089.
  • Guijas, C.; Montenegro-Burke, J. R.; Domingo-Almenara, X.; Palermo, A.; Warth, B.; Hermann, G.; Koellensperger, G.; Huan, T.; Uritboonthai, W.; Aisporna, A. E.; et al. METLIN: A Technology Platform for Identifying Knowns and Unknowns. Anal. Chem. 2018, 90, 3156–3164. DOI: 10.1021/acs.analchem.7b04424.
  • Ren, S.; Hinzman, A. A.; Kang, E. L.; Szczesniak, R. D.; Lu, L. J. Computational and Statistical Analysis of Metabolomics Data. Metabolomics 2015, 11, 1492–1513. DOI: 10.1007/s11306-015-0823-6.
  • Sevin, D. C.; Kuehne, A.; Zamboni, N.; Sauer, U. Biological Insights through Nontargeted Metabolomics. Curr. Opin. Biotechnol. 2015, 34, 1–8. DOI: 10.1016/j.copbio.2014.10.001.
  • Chong, J.; Soufan, O.; Li, C.; Caraus, I.; Li, S.; Bourque, G.; Wishart, D. S.; Xia, J. MetaboAnalyst 4.0: Towards More Transparent and Integrative Metabolomics Analysis. Nucleic Acids Res. 2018, 46, W486–W494. DOI: 10.1093/nar/gky310.
  • Liang, D. D.; Liu, Q.; Zhou, K. J.; Jia, W.; Xie, G. X.; Chen, T. L. IP4M: An Integrated Platform for Mass Spectrometry-Based Metabolomics Data Mining. BMC Bioinformatics 2020, 21, 444–444. DOI: 10.1186/s12859-020-03786-x.
  • Embade, N.; Marino, Z.; Diercks, T.; Cano, A.; Lens, S.; Cabrera, D.; Navasa, M.; Falcon-Perez, J. M.; Caballeria, J.; Castro, A.; et al. Metabolic Characterization of Advanced Liver Fibrosis in HCV Patients as Studied by Serum 1H-NMR Spectroscopy. PLoS One 2016, 11, e0155094. DOI: 10.1371/journal.pone.0155094.
  • Sands, C. J.; Guha, I. N.; Kyriakides, M.; Wright, M.; Beckonert, O.; Holmes, E.; Rosenberg, W. M.; Coen, M. Metabolic Phenotyping for Enhanced Mechanistic Stratification of Chronic Hepatitis C-Induced Liver Fibrosis. Am. J. Gastroenterol. 2015, 110, 159–169. DOI: 10.1038/ajg.2014.370.
  • Simillion, C.; Semmo, N.; Idle, J.; Beyoğlu, D. Robust Regression Analysis of GCMS Data Reveals Differential Rewiring of Metabolic Networks in Hepatitis B and C Patients. Metabolites 2017, 7, 51. DOI: 10.3390/metabo7040051.
  • Zheng, H.; Chen, M. J.; Lu, S. M.; Zhao, L. C.; Ji, J. S.; Gao, H. C. Metabolic Characterization of Hepatitis B Virus-Related Liver Cirrhosis Using NMR-Based Serum Metabolomics. Metabolomics 2017, 13, 9. DOI: 10.1007/s11306-017-1260-5.
  • Harada, S.; Takebayashi, T.; Kurihara, A.; Akiyama, M.; Suzuki, A.; Hatakeyama, Y.; Sugiyama, D.; Kuwabara, K.; Takeuchi, A.; Okamura, T.; et al. Metabolomic Profiling Reveals Novel Biomarkers of Alcohol Intake and Alcohol-Induced Liver Injury in Community-Dwelling Men. Environ. Health Prev. Med. 2016, 21, 18–26. DOI: 10.1007/s12199-015-0494-y.
  • Liang, Q.; Wang, C.; Li, B.; Zhang, A-h. Metabolomics of Alcoholic Liver Disease: A Clinical Discovery Study. RSC Adv. 2015, 5, 80381–80387. DOI: 10.1039/C5RA13417J.
  • Rodriguez-Gallego, E.; Fernandez-Arroyo, S.; Riera-Borrull, M.; Hernandez-Aguilera, A.; Guirro, M.; Marine-Casado, R.; Luciano-Mateo, F.; Garcia-Heredia, A.; Marti-Lindez, A. A.; Beltran-Debon, R.; et al. Metabolomics Reveals That Alterations in Circulating A-Ketoglutarate May Be Relevant in the Assessment of Morbid Obesity-Associated Nonalcoholic Fatty Liver Disease. Atherosclerosis 2014, 235, E65. DOI: 10.1016/j.atherosclerosis.2014.05.163.
  • Rodriguez-Gallego, E.; Guirro, M.; Riera-Borrull, M.; Hernandez-Aguilera, A.; Marine-Casado, R.; Fernandez-Arroyo, S.; Beltran-Debon, R.; Sabench, F.; Hernandez, M.; del Castillo, D.; et al. Mapping of the Circulating Metabolome Reveals α-Ketoglutarate as a Predictor of Morbid Obesity-Associated Non-Alcoholic Fatty Liver Disease. Int. J. Obes. (Lond) 2015, 39, 279–287. DOI: 10.1038/ijo.2014.53.
  • Chen, T.; Xie, G.; Wang, X.; Fan, J.; Qiu, Y.; Zheng, X.; Qi, X.; Cao, Y.; Su, M.; Wang, X.; et al. Serum and Urine Metabolite Profiling Reveals Potential Biomarkers of Human Hepatocellular Carcinoma. Mol. Cell Proteomics 2011, 10, M110 004945. DOI: 10.1074/mcp.M110.004945..
  • Clarke, J. D.; Novak, P.; Lake, A. D.; Shipkova, P.; Aranibar, N.; Robertson, D.; Severson, P. L.; Reily, M. D.; Futscher, B. W.; Lehman-McKeeman, L. D.; et al. Characterization of Hepatocellular Carcinoma Related Genes and Metabolites in Human Nonalcoholic Fatty Liver Disease. Dig. Dis. Sci. 2014, 59, 365–374. DOI: 10.1007/s10620-013-2873-9.
  • Li, Y. H.; Woo, S. H.; Choi, D. H.; Cho, E. H. Succinate Causes α-SMA Production Through GPR91 Activation in Hepatic Stellate Cells. Biochem. Biophys. Res. Commun. 2015, 463, 853–858. DOI: 10.1016/j.bbrc.2015.06.023.
  • Schofield, Z.; Reed, M. A. C.; Newsome, P. N.; Adams, D. H.; Gunther, U. L.; Lalor, P. F. Changes in Human Hepatic Metabolism in Steatosis and Cirrhosis. World J. Gastroenterol. 2017, 23, 2685–2695. DOI: 10.3748/wjg.v23.i15.2685.
  • Sookoian, S.; Castano, G. O.; Scian, R.; Gianotti, T. F.; Dopazo, H.; Rohr, C.; Gaj, G.; San Martino, J.; Sevic, I.; Flichman, D.; et al. Serum Aminotransferases in Nonalcoholic Fatty Liver Disease Are a Signature of Liver Metabolic Perturbations at the Amino Acid and Krebs Cycle Level. Am. J. Clin. Nutr. 2016, 103, 422–434. DOI: 10.3945/ajcn.115.118695.
  • Rui, L. Y. Energy Metabolism in the Liver. Compr. Physiol. 2014, 4, 177–197. DOI: 10.1002/cphy.c130024.
  • Dong, S.; Zhan, Z. Y.; Cao, H. Y.; Wu, C.; Bian, Y. Q.; Li, J. Y.; Cheng, G. H.; Liu, P.; Sun, M. Y. Urinary Metabolomics Analysis Identifies Key Biomarkers of Different Stages of Nonalcoholic Fatty Liver Disease. World J. Gastroenterol. 2017, 23, 2771–2784. DOI: 10.3748/wjg.v23.i15.2771.
  • Semmo, N.; Weber, T.; Idle, J. R.; Beyoğlu, D. Metabolomics Reveals That Aldose Reductase Activity Due to AKR1B10 is Upregulated in Hepatitis C Virus Infection. J. Viral Hepat. 2015, 22, 617–624. DOI: 10.1111/jvh.12376.
  • Subramanian, V.; Byrne, J. J.; Kaye, P.; Daykin, C. A.; Aithal, G. P. Serum Metabolomics Reveals Novel Metabolic Markers of Non Alcoholic Fatty Liver Disease. Hepatology 2008, 48, 811A–811A. DOI: 10.1111/j.1523-5378.2008.00626.x.
  • Nguyen, P.; Leray, V.; Diez, M.; Serisier, S.; Le Bloc'h, J.; Siliart, B.; Dumon, H. Liver Lipid Metabolism. J. Anim. Physiol. Anim. Nutr. (Berl) 2008, 92, 272–283. DOI: 10.1111/j.1439-0396.2007.00752.x.
  • Dong, V.; Nanchal, R.; Karvellas, C. J. Pathophysiology of Acute Liver Failure. Nutr. Clin. Pract. 2020, 35, 24–29. DOI: 10.1002/ncp.10459.
  • Montagner, A.; Polizzi, A.; Fouché, E.; Ducheix, S.; Lippi, Y.; Lasserre, F.; Barquissau, V.; Régnier, M.; Lukowicz, C.; Benhamed, F.; et al. Liver PPARα Is Crucial for Whole-Body Fatty Acid Homeostasis and Is Protective Against NAFLD. Gut 2016, 65, 1202–1214. DOI: 10.1136/gutjnl-2015-310798.
  • Kaikkonen, J. E.; Würtz, P.; Suomela, E.; Lehtovirta, M.; Kangas, A. J.; Jula, A.; Mikkilä, V.; Viikari, J. S. A.; Juonala, M.; Rönnemaa, T.; et al. Metabolic Profiling of Fatty Liver in Young and Middle-Aged Adults: Cross-Sectional and Prospective Analyses of the Young Finns Study. Hepatology 2017, 65, 491–500. DOI: 10.1002/hep.28899.
  • Pietzner, M.; Budde, K.; Homuth, G.; Kastenmuller, G.; Henning, A. K.; Artati, A.; Krumsiek, J.; Volzke, H.; Adamski, J.; Lerch, M. M.; et al. Hepatic Steatosis is Associated with Adverse Molecular Signatures in Subjects without Diabetes. J. Clin. Endocrinol. Metab. 2018, 103, 3856–3868. DOI: 10.1210/jc.2018-00999.
  • Jin, R.; Banton, S.; Tran, V. T.; Konomi, J. V.; Li, S.; Jones, D. P.; Vos, M. B. Amino Acid Metabolism is Altered in Adolescents with Nonalcoholic Fatty Liver Disease-An Untargeted, High Resolution Metabolomics Study. J. Pediatr. 2016, 172, 14–19.e15. DOI: 10.1016/j.jpeds.2016.01.026.
  • Li, C.; Li, L.; Lian, J.; Watts, R.; Nelson, R.; Goodwin, B.; Lehner, R. Roles of Acyl-CoA:Diacylglycerol Acyltransferases 1 and 2 in Triacylglycerol Synthesis and Secretion in Primary Hepatocytes. Arterioscler. Thromb. Vasc. Biol. 2015, 35, 1080–1091. DOI: 10.1161/ATVBAHA.114.304584.
  • Chen, S.; Yin, P.; Zhao, X.; Xing, W.; Hu, C.; Zhou, L.; Xu, G. Serum Lipid Profiling of Patients with Chronic Hepatitis B, Cirrhosis, and Hepatocellular Carcinoma by Ultra Fast LC/IT-TOF MS. Electrophoresis 2013, 34, 2848–2856. DOI: 10.1002/elps.201200629.
  • Zhou, Y.; Llaurado, G.; Oresic, M.; Hyotylainen, T.; Orho-Melander, M.; Yki-Jarvinen, H. Circulating Triacylglycerol Signatures and Insulin Sensitivity in NAFLD Associated with the E167K Variant in TM6SF2. J. Hepatol. 2015, 62, 657–663. DOI: 10.1016/j.jhep.2014.10.010.
  • Corbin, K. D.; Zeisel, S. H. Choline Metabolism Provides Novel Insights into Nonalcoholic Fatty Liver Disease and Its Progression. Curr. Opin. Gastroenterol. 2012, 28, 159–165. DOI: 10.1097/MOG.0b013e32834e7b4b.
  • Sherriff, J. L.; O'Sullivan, T. A.; Properzi, C.; Oddo, J. L.; Adams, L. A. Choline, Its Potential Role in Nonalcoholic Fatty Liver Disease, and the Case for Human and Bacterial Genes. Adv. Nutr. 2016, 7, 5–13. DOI: 10.3945/an.114.007955.
  • Cheung, O.; Sanyal, A. J. Recent Advances in Nonalcoholic Fatty Liver Disease. Curr. Opin. Gastroenterol. 2010, 26, 202–208. DOI: 10.1097/MOG.0b013e328337b0c4.
  • Ueland, P. M. Choline and Betaine in Health and Disease. J. Inherit. Metab. Dis. 2011, 34, 3–15. DOI: 10.1007/s10545-010-9088-4.
  • Li, Z.; Agellon, L. B.; Allen, T. M.; Umeda, M.; Jewell, L.; Mason, A.; Vance, D. E. The Ratio of Phosphatidylcholine to Phosphatidylethanolamine Influences Membrane Integrity and Steatohepatitis. Cell Metab. 2006, 3, 321–331. DOI: 10.1016/j.cmet.2006.03.007.
  • Cano, A.; Marino, Z.; Millet, O.; Martinez-Arranz, I.; Navasa, M.; Falcon-Perez, J. M.; Perez-Cormenzana, M.; Caballeria, J.; Embade, N.; Forns, X.; et al. A Metabolomics Signature Linked to Liver Fibrosis in the Serum of Transplanted Hepatitis C Patients. Sci. Rep. 2017, 7, 10497. DOI: 10.1038/s41598-017-10807-y.
  • Feldman, A.; Eder, S. K.; Felder, T. K.; Kedenko, L.; Paulweber, B.; Stadlmayr, A.; Huber-Schonauer, U.; Niederseer, D.; Stickel, F.; Auer, S.; et al. Clinical and Metabolic Characterization of Lean Caucasian Subjects with Non-Alcoholic Fatty Liver. Am. J. Gastroenterol. 2017, 112, 102–110. DOI: 10.1038/ajg.2016.318.
  • Krautbauer, S.; Eisinger, K.; Wiest, R.; Liebisch, G.; Buechler, C. Systemic Saturated Lysophosphatidylcholine is Associated with Hepatic Function in Patients with Liver Cirrhosis. Prostaglandins Other Lipid Mediat. 2016, 124, 27–33. DOI: 10.1016/j.prostaglandins.2016.06.001.
  • Suciu, A. M.; Crisan, D. A.; Procopet, B. D.; Radu, C. I.; Socaciu, C.; Tantau, M. V.; Stefanescu, H. O.; Grigorescu, M. What's in Metabolomics for Alcoholic Liver Disease? J. Gastrointestin. Liver Dis. 2018, 27, 51–58. DOI: 10.15403/jgld.2014.1121.271.ald.
  • Day, C. R.; Kempson, S. A. Betaine Chemistry, Roles, and Potential Use in Liver Disease. Biochim. Biophys. Acta 2016, 1860, 1098–1106. DOI: 10.1016/j.bbagen.2016.02.001.
  • Mazi, T. A.; Sarode, G. V.; Czlonkowska, A.; Litwin, T.; Kim, K.; Shibata, N. M.; Medici, V. Dysregulated Choline, Methionine, and Aromatic Amino Acid Metabolism in Patients with Wilson Disease: Exploratory Metabolomic Profiling and Implications for Hepatic and Neurologic Phenotypes. Int. J. Mol. Sci. 2019, 20, 5937. DOI: 10.3390/ijms20235937.
  • Schoeman, J. C.; Hou, J.; Harms, A. C.; Vreeken, R. J.; Berger, R.; Hankemeier, T.; Boonstra, A. Metabolic Characterization of the Natural Progression of Chronic Hepatitis B. Genome Med. 2016, 8, 64. DOI: 10.1186/s13073-016-0318-8.
  • Sookoian, S.; Puri, P.; Castano, G. O.; Scian, R.; Mirshahi, F.; Sanyal, A. J.; Pirola, C. J. Nonalcoholic Steatohepatitis is Associated with a State of Betaine-Insufficiency. Liver Int. 2017, 37, 611–619. DOI: 10.1111/liv.13249.
  • Grammatikos, G.; Muhle, C.; Ferreiros, N.; Schroeter, S.; Bogdanou, D.; Schwalm, S.; Hintereder, G.; Kornhuber, J.; Zeuzem, S.; Sarrazin, C.; et al. Serum Acid Sphingomyelinase is Upregulated in Chronic Hepatitis C Infection and Non Alcoholic Fatty Liver Disease. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2014, 1841, 1012–1020. DOI: 10.1016/j.bbalip.2014.04.007.
  • Kolter, T. A View on Sphingolipids and Disease. Chem. Phys. Lipids 2011, 164, 590–606. DOI: 10.1016/j.chemphyslip.2011.04.013.
  • Papandreou, C.; Bullo, M.; Tinahones, F. J.; Martinez-Gonzalez, M. A.; Corella, D.; Fragkiadakis, G. A.; Lopez-Miranda, J.; Estruch, R.; Fito, M.; Salas-Salvado, J. Serum Metabolites in Non-Alcoholic Fatty-Liver Disease Development or Reversion; A Targeted Metabolomic Approach within the PREDIMED Trial. Nutr. Metab. 2017, 14, 58. DOI: 10.1186/s12986-017-0213-3.
  • Arab, J. P.; Karpen, S. J.; Dawson, P. A.; Arrese, M.; Trauner, M. Bile Acids and Nonalcoholic Fatty Liver Disease: Molecular Insights and Therapeutic Perspectives. Hepatology 2017, 65, 350–362. DOI: 10.1002/hep.28709.
  • Staels, B.; Fonseca, V. A. Bile Acids and Metabolic Regulation Mechanisms and Clinical Responses to Bile Acid Sequestration. Diabetes Care 2009, 32, S237–S245. DOI: 10.2337/dc09-S355.
  • Lake, A. D.; Novak, P.; Shipkova, P.; Aranibar, N.; Robertson, D.; Reily, M. D.; Lu, Z.; Lehman-McKeeman, L. D.; Cherrington, N. J. Decreased Hepatotoxic Bile Acid Composition and Altered Synthesis in Progressive Human Nonalcoholic Fatty Liver Disease. Toxicol. Appl. Pharmacol. 2013, 268, 132–140. DOI: 10.1016/j.taap.2013.01.022.
  • Troisi, J.; Masarone, M.; Aglitti, A.; Di Zenzo, C.; Rosato, V.; Persico, M. Metabolomics in the Progression of Non Alcoholic Fatty Liver Disease. Dig. Liver Dis. 2018, 50, 18–18. DOI: 10.1016/j.dld.2018.01.036.
  • Gaggini, M.; Carli, F.; Rosso, C.; Buzzigoli, E.; Marietti, M.; Della Latta, V.; Ciociaro, D.; Abate, M. L.; Gambino, R.; Cassader, M.; et al. Altered Amino Acid Concentrations in NAFLD: Impact of Obesity and Insulin Resistance. Hepatology 2018, 67, 145–158. DOI: 10.1002/hep.29465.
  • Cheng, S.; Wiklund, P.; Autio, R.; Borra, R.; Ojanen, X.; Xu, L.; Tormakangas, T.; Alen, M. Adipose Tissue Dysfunction and Altered Systemic Amino Acid Metabolism Are Associated with Non-Alcoholic Fatty Liver Disease. PLoS One 2015, 10, e0138889. DOI: 10.1371/journal.pone.0138889.
  • Dejong, C. H. C.; van de Poll, M. C. G.; Soeters, P. B.; Jalan, R.; Damink, S. Aromatic Amino Acid Metabolism during Liver Failure. J. Nutr. 2007, 137, 1579S–1585S. DOI: 10.1093/jn/137.6.1579S.
  • Sunny, N. E.; Kalavalapalli, S.; Bril, F.; Garrett, T. J.; Nautiyal, M.; Mathew, J. T.; Williams, C. M.; Cusi, K. Cross-Talk between Branched-Chain Amino Acids and Hepatic Mitochondria is Compromised in Nonalcoholic Fatty Liver Disease. Am. J. Physiol. Endocrinol. Metab. 2015, 309, E311–E319. DOI: 10.1152/ajpendo.00161.2015.
  • Wang, J.; Wang, Y.; Zhang, X.; Liu, J. Q.; Zhang, Q. P.; Zhao, Y.; Peng, J. H.; Feng, Q.; Dai, J. Y.; Sun, S. J.; et al. Gut Microbial Dysbiosis is Associated with Altered Hepatic Functions and Serum Metabolites in Chronic Hepatitis B Patients. Front. Microbiol. 2017, 8, 12. DOI: 10.3389/fmicb.2017.02222.
  • Yaplito-Lee, J.; Chow, C. W.; Boneh, A. Histopathological Findings in Livers of Patients with Urea Cycle Disorders. Mol. Genet. Metab. 2013, 108, 161–165. DOI: 10.1016/j.ymgme.2013.01.006.
  • Brosnan, J. T.; Brosnan, M. E. Creatine Metabolism and the Urea Cycle. Mol. Genet. Metab. 2010, 100 Suppl 1, S49–S52. DOI: 10.1016/j.ymgme.2010.02.020.
  • Soga, T.; Sugimoto, M.; Honma, M.; Mori, M.; Igarashi, K.; Kashikura, K.; Ikeda, S.; Hirayama, A.; Yamamoto, T.; Yoshida, H.; et al. Serum Metabolomics Reveals γ-Glutamyl Dipeptides as Biomarkers for Discrimination among Different Forms of Liver Disease. J. Hepatol. 2011, 55, 896–905. DOI: 10.1016/j.jhep.2011.01.031.
  • Lu, S. C. Regulation of Glutathione Synthesis. Mol. Aspects Med. 2009, 30, 42–59. DOI: 10.1016/j.mam.2008.05.005.
  • Yuan, L. Y.; Kaplowitz, N. Glutathione in Liver Diseases and Hepatotoxicity. Mol. Aspects Med. 2009, 30, 29–41. DOI: 10.1016/j.mam.2008.08.003.
  • Quintás, G.; Portillo, N.; García-Cañaveras, J. C.; Castell, J. V.; Ferrer, A.; Lahoz, A. Chemometric Approaches to Improve PLSDA Model Outcome for Predicting Human Non-Alcoholic Fatty Liver Disease Using UPLC-MS as a Metabolic Profiling Tool. Metabolomics 2012, 8, 86–98. DOI: 10.1007/s11306-011-0292-5.
  • Fustin, J.-M.; Doi, M.; Yamada, H.; Komatsu, R.; Shimba, S.; Okamura, H. Rhythmic Nucleotide Synthesis in the Liver: Temporal Segregation of Metabolites. Cell Rep. 2012, 1, 341–349. DOI: 10.1016/j.celrep.2012.03.001.
  • Biliotti, E.; Tomassini, A.; Palazzo, D.; Capuani, G.; Sciubba, F.; Esvan, R.; De Angelis, M.; Franchi, C.; Iaiani, G.; Maida, P.; et al. Urinary Metabotypes in Patients with Chronic Hepatitis C Virus Infection as Revealed by Nuclear Magnetic Resonance-Based Metabolomics. J. Hepatol. 2017, 66, S236–S237. DOI: 10.1016/S0168-8278(17)30778-X.
  • Le, T. T.; Ziemba, A.; Urasaki, Y.; Hayes, E.; Brotman, S.; Pizzorno, G. Disruption of Uridine Homeostasis Links Liver Pyrimidine Metabolism to Lipid Accumulation. J. Lipid Res. 2013, 54, 1044–1057. DOI: 10.1194/jlr.M034249.
  • Lawitz, E. J.; Coste, A.; Poordad, F.; Alkhouri, N.; Loo, N.; McColgan, B. J.; Tarrant, J. M.; Nguyen, T.; Han, L.; Chung, C.; et al. Acetyl-CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients with Nonalcoholic Steatohepatitis. Clin. Gastroenterol. Hepatol. 2018, 16, 1983–1991.e1983. DOI: 10.1016/j.cgh.2018.04.042.
  • Loomba, R.; Kayali, Z.; Noureddin, M.; Ruane, P.; Lawitz, E. J.; Bennett, M.; Wang, L. L.; Harting, E.; Tarrant, J. M.; McColgan, B. J.; et al. GS-0976 Reduces Hepatic Steatosis and Fibrosis Markers in Patients with Nonalcoholic Fatty Liver Disease. Gastroenterology 2018, 155, 1463–1473.e6. DOI: 10.1053/j.gastro.2018.07.027.
  • Okuno, M.; Kim, M. K.; Mizu, M.; Mori, M.; Mori, H.; Yamori, Y. Palatinose-Blended Sugar Compared with Sucrose: Different Effects on Insulin Sensitivity after 12 Weeks Supplementation in Sedentary Adults. Int. J. Food Sci. Nutr. 2010, 61, 643–651. DOI: 10.3109/09637481003694576.
  • Kawaguchi, T.; Nakano, D.; Oriishi, T.; Torimura, T. Effects of Isomaltulose on Insulin Resistance and Metabolites in Patients with Non‑Alcoholic Fatty Liver Disease: A Metabolomic Analysis. Mol. Med. Rep. 2018, 18, 2033–2042. DOI: 10.3892/mmr.2018.9223.
  • Abenavoli, L.; Greco, M.; Nazionale, I.; Peta, V.; Milic, N.; Accattato, F.; Foti, D.; Gulletta, E.; Luzza, F. Effects of Mediterranean Diet Supplemented with Silybin-Vitamin E-Phospholipid Complex in Overweight Patients with Non-Alcoholic Fatty Liver Disease. Expert Rev. Gastroenterol. Hepatol. 2015, 9, 519–527. DOI: 10.1586/17474124.2015.1004312.
  • Stiuso, P.; Scognamiglio, I.; Murolo, M.; Ferranti, P.; De Simone, C.; Rizzo, M. R.; Tuccillo, C.; Caraglia, M.; Loguercio, C.; Federico, A. Serum Oxidative Stress Markers and Lipidomic Profile to Detect NASH Patients Responsive to an Antioxidant Treatment: A Pilot Study. Oxid. Med. Cell. Longev. 2014, 2014, 1–8. DOI: 10.1155/2014/169216.
  • Nagashimada, M.; Ota, T. Role of Vitamin E in Nonalcoholic Fatty Liver Disease. IUBMB Life 2019, 71, 516–522. DOI: 10.1002/iub.1991.
  • Cheng, J.; Joyce, A.; Yates, K.; Aouizerat, B.; Sanyal, A. J. Metabolomic Profiling to Identify Predictors of Response to Vitamin E for Non-Alcoholic Steatohepatitis (NASH). PLoS One 2012, 7, e44106. DOI: 10.1371/journal.pone.0044106.

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