{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T08:54:59Z","timestamp":1772787299213,"version":"3.50.1"},"reference-count":112,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,9]],"date-time":"2021-10-09T00:00:00Z","timestamp":1633737600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ACCI\u00d3","award":["ACCI\u00d3-Eurecat"],"award-info":[{"award-number":["ACCI\u00d3-Eurecat"]}]},{"name":"TECNOMIFOOD; Centre for the Development of Industrial Technology (CDTI)","award":["CER-20191010"],"award-info":[{"award-number":["CER-20191010"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have emerged as the leading causes of chronic liver disease in the world. Obesity, insulin resistance, and dyslipidemia are multifactorial risk factors strongly associated with NAFLD\/NASH. Here, a specific combination of metabolic cofactors (a multi-ingredient; MI) containing precursors of glutathione (GSH) and nicotinamide adenine dinucleotide (NAD+) (betaine, N-acetyl-cysteine, L-carnitine and nicotinamide riboside) was evaluated as effective treatment for the NAFLD\/NASH pathophysiology. Six-week-old male mice were randomly divided into control diet animals and animals exposed to a high fat and high fructose\/sucrose diet to induce NAFLD. After 16 weeks, diet-induced NAFLD mice were distributed into two groups, treated with the vehicle (HFHFr group) or with a combination of metabolic cofactors (MI group) for 4 additional weeks, and blood and liver were obtained from all animals for biochemical, histological, and molecular analysis. The MI treatment reduced liver steatosis, decreasing liver weight and hepatic lipid content, and liver injury, as evidenced by a pronounced decrease in serum levels of liver transaminases. Moreover, animals supplemented with the MI cocktail showed a reduction in the gene expression of some proinflammatory cytokines when compared with their HFHFr counterparts. In addition, MI supplementation was effective in decreasing hepatic fibrosis and improving insulin sensitivity, as observed by histological analysis, as well as a reduction in fibrotic gene expression (Col1\u03b11) and improved Akt activation, respectively. Taken together, supplementation with this specific combination of metabolic cofactors ameliorates several features of NAFLD, highlighting this treatment as a potential efficient therapy against this disease in humans.<\/jats:p>","DOI":"10.3390\/nu13103532","type":"journal-article","created":{"date-parts":[[2021,10,10]],"date-time":"2021-10-10T21:37:29Z","timestamp":1633901849000},"page":"3532","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Supplementation with a Specific Combination of Metabolic Cofactors Ameliorates Non-Alcoholic Fatty Liver Disease, Hepatic Fibrosis, and Insulin Resistance in Mice"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6588-1193","authenticated-orcid":false,"given":"Sergio","family":"Quesada-V\u00e1zquez","sequence":"first","affiliation":[{"name":"Eurecat, Technology Centre of Catalunya, Nutrition and Health Unit, 43204 Reus, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Colom-Pellicer","sequence":"additional","affiliation":[{"name":"Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, 43007 Tarragona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c8lia","family":"Navarro-Masip","sequence":"additional","affiliation":[{"name":"Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, 43007 Tarragona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8657-5726","authenticated-orcid":false,"given":"Gerard","family":"Aragon\u00e8s","sequence":"additional","affiliation":[{"name":"Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili, 43007 Tarragona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josep M.","family":"Del Bas","sequence":"additional","affiliation":[{"name":"Eurecat, Technology Centre of Catalunya, Nutrition and Health Unit, 43204 Reus, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6144-0294","authenticated-orcid":false,"given":"Antoni","family":"Caimari","sequence":"additional","affiliation":[{"name":"Eurecat, Centre Tecnol\u00f2gic de Catalunya, Biotechnology Area, 43204 Reus, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1172-3995","authenticated-orcid":false,"given":"Xavier","family":"Escot\u00e9","sequence":"additional","affiliation":[{"name":"Eurecat, Technology Centre of Catalunya, Nutrition and Health Unit, 43204 Reus, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Quesada-V\u00e1zquez, S., Aragon\u00e8s, G., del Bas, J.M., and Escot\u00e9, X. (2020). Diet, Gut Microbiota and Non-Alcoholic Fatty Liver Disease: Three Parts of the Same Axis. Cells, 9.","DOI":"10.3390\/cells9010176"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S47","DOI":"10.1016\/j.jhep.2014.12.012","article-title":"NAFLD: A Multisystem Disease","volume":"62","author":"Byrne","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.jhep.2009.03.019","article-title":"Systematic Review of Risk Factors for Fibrosis Progression in Non-Alcoholic Steatohepatitis","volume":"51","author":"Argo","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1007\/s11901-019-00500-1","article-title":"NAFLD Histology: A Critical Review and Comparison of Scoring Systems","volume":"18","author":"Pai","year":"2019","journal-title":"Curr. Hepatol. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Mardinoglu, A., Ural, D., Zeybel, M., Yuksel, H.H., Uhl\u00e9n, M., and Bor\u00e9n, J. (2019). The Potential Use of Metabolic Cofactors in Treatment of NAFLD. Nutrients, 11.","DOI":"10.3390\/nu11071578"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"9547613","DOI":"10.1155\/2018\/9547613","article-title":"Review Article Role of Oxidative Stress in Pathophysiology of Nonalcoholic Fatty Liver Disease","volume":"11","author":"Masarone","year":"2018","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15252\/msb.209495","article-title":"The Acute Effect of Metabolic Cofactor Supplementation: A Potential Therapeutic Strategy against Non-alcoholic Fatty Liver Disease","volume":"16","author":"Zhang","year":"2020","journal-title":"Mol. Syst. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3407","DOI":"10.3748\/wjg.v23.i19.3407","article-title":"Relationship between Adipose Tissue Dysfunction, Vitamin D Deficiency and the Pathogenesis of Non-Alcoholic Fatty Liver Disease","volume":"23","author":"Cimini","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.metabol.2015.12.012","article-title":"The Multiple-Hit Pathogenesis of Non-Alcoholic Fatty Liver Disease (NAFLD)","volume":"65","author":"Buzzetti","year":"2016","journal-title":"Metab. Clin. Exp."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Marin, V., Gazzin, S., Gambaro, S.E., Ben, M.D., Calligaris, S., Anese, M., Raseni, A., Avellini, C., Giraudi, P.J., and Tiribelli, C. (2017). Effects of Oral Administration of Silymarin in a Juvenile Murine Model of Non-Alcoholic Steatohepatitis. Nutrients, 9.","DOI":"10.3390\/nu9091006"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1155\/2012\/725468","article-title":"Current Treatment Options for Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis","volume":"26","author":"Beaton","year":"2012","journal-title":"Can. J. Gastroenterol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/S2468-1253(19)30419-4","article-title":"Prevalence of Steatosis and Fibrosis in Young Adults in the UK: A Population-Based Study","volume":"5","author":"Abeysekera","year":"2020","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Su\u00e1rez, M., Boqu\u00e9, N., Del Bas, J.M., Mayneris-Perxachs, J., Arola, L., and Caimari, A. (2017). Mediterranean Diet and Multi-Ingredient-Based Interventions for the Management of Non-Alcoholic Fatty Liver Disease. Nutrients, 9.","DOI":"10.3390\/nu9101052"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"916","DOI":"10.15252\/msb.20167422","article-title":"Personal Model-assisted Identification of NAD+ and Glutathione Metabolism as Intervention Target in NAFLD","volume":"13","author":"Mardinoglu","year":"2017","journal-title":"Mol. Syst. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3083","DOI":"10.1038\/ncomms4083","article-title":"Genome-Scale Metabolic Modelling of Hepatocytes Reveals Serine Deficiency in Patients with Non-Alcoholic Fatty Liver Disease","volume":"5","author":"Mardinoglu","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1758-5996-3-31","article-title":"L-Carnitine Ameliorated Fatty Liver in High-Calorie Diet\/STZ-Induced Type 2 Diabetic Mice by Improving Mitochondrial Function","volume":"3","author":"Xia","year":"2011","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1016\/j.cmet.2012.04.022","article-title":"The NAD+ Precursor Nicotinamide Riboside Enhances Oxidative Metabolism and Protects against High-Fat Diet-Induced Obesity","volume":"15","author":"Houtkooper","year":"2012","journal-title":"Cell Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1016\/j.biopha.2018.04.154","article-title":"Betaine Protects Mice against Acetaminophen Hepatotoxicity Possibly via Mitochondrial Complex II and Glutathione Availability","volume":"103","author":"Khodayar","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Marin, V., Rosso, N., Dal Ben, M., Raseni, A., Boschelle, M., Degrassi, C., Nemeckova, I., Nachtigal, P., Avellini, C., and Tiribelli, C. (2016). An Animal Model for the Juvenile Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0158817"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"574832","DOI":"10.1155\/2015\/574832","article-title":"Nonalcoholic Steatohepatitis: A Search for Factual Animal Models","volume":"2015","author":"Sanches","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_21","first-page":"167","article-title":"Pathogenesis and Prevention of Hepatic Steatosis","volume":"11","author":"Nassir","year":"2015","journal-title":"Gastroenterol. Hepatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1096\/fj.07-9574LSF","article-title":"Dose Translation from Animal to Human Studies Revisited","volume":"22","author":"Nihal","year":"2008","journal-title":"FASEB J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/ijo.2012.75","article-title":"Low Doses of Grape Seed Procyanidins Reduce Adiposity and Improve the Plasma Lipid Profile in Hamsters","volume":"37","author":"Caimari","year":"2013","journal-title":"Int. J. Obes."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.ab.2005.05.009","article-title":"A Procedure for Measuring Triacylglyceride and Cholesterol Content Using a Small Amount of Tissue","volume":"343","year":"2005","journal-title":"Anal. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Liang, W., Menke, A.L., Driessen, A., Koek, G.H., and Lindeman, J.H. (2014). Establishment of a General NAFLD Scoring System for Rodent Models and Comparison to Human Liver Pathology. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0115922"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.bpg.2011.02.005","article-title":"Mechanisms of Hepatic Fibrogenesis","volume":"25","author":"Lee","year":"2011","journal-title":"Best Pr. Res. Clin. Gastroenterol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1111\/liv.12184","article-title":"Image Analysis of Liver Collagen Using Sirius Red Is More Accurate and Correlates Better with Serum Fibrosis Markers than Trichrome","volume":"33","author":"Huang","year":"2013","journal-title":"Liver Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1007\/BF01003791","article-title":"The Masson Staining of Collagen\u2014An Explanation of an Apparent Paradox","volume":"7","author":"Flint","year":"1975","journal-title":"Histochem. J."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Yang, J., Neira, S., Elisa, F., Gil-iturbe, E., Castilla-madrigal, R., Fern, M., Mart, J.A., and Moreno-aliaga, M.J. (2021). Effects of Long-Term DHA Supplementation and Physical Aged Female Mice. Nutrients, 13.","DOI":"10.3390\/nu13020501"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4711","DOI":"10.1038\/ncomms5711","article-title":"IL-37 Protects against Obesity-Induced Inflammation and Insulin Resistance","volume":"5","author":"Ballak","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Antraco, V.J., Hirata, B.K.S., de Jesus Sim\u00e3o, J., Cruz, M.M., da Silva, V.S., de S\u00e1, R.D.C., Abdala, F.M., Armelin-Correa, L., and Alonso-Vale, M.I.C. (2021). Omega-3 Polyunsaturated Fatty Acids Prevent Nonalcoholic Steatohepatitis (Nash) and Stimulate Adipogenesis. Nutrients, 13.","DOI":"10.3390\/nu13020622"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2634","DOI":"10.1194\/jlr.M055335","article-title":"Cardiotrophin-1 Stimulates Lipolysis through the Regulation of Main Adipose Tissue Lipases","volume":"55","author":"Laiglesia","year":"2014","journal-title":"J. Lipid Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/ijo.2009.290","article-title":"Relation between Human LPIN1, Hypoxia and Endoplasmic Reticulum Stress Genes in Subcutaneous and Visceral Adipose Tissue","volume":"34","author":"Miranda","year":"2010","journal-title":"Int. J. Obes."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1136\/gutjnl-2015-310798","article-title":"Liver PPAR\u03b1 Is Crucial for Whole-Body Fatty Acid Homeostasis and Is Protective against NAFLD","volume":"65","author":"Montagner","year":"2016","journal-title":"Gut"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1053\/j.gastro.2007.11.037","article-title":"Hepatic Fatty Acid Transporter Cd36 Is a Common Target of LXR, PXR, and PPAR\u03b3 in Promoting Steatosis","volume":"134","author":"Zhou","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.abb.2017.06.017","article-title":"Polydatin Protects against Carbon Tetrachloride-Induced Liver Fibrosis in Mice","volume":"629","author":"Zhao","year":"2017","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/s41598-017-18981-9","article-title":"SPARC Expression Is Associated with Hepatic Injury in Rodents and Humans with Non-Alcoholic Fatty Liver Disease","volume":"8","author":"Mazzolini","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"564674","DOI":"10.3389\/fonc.2020.564674","article-title":"Emodin Inhibits Inflammation, Carcinogenesis, and Cancer Progression in the AOM\/DSS Model of Colitis-Associated Intestinal Tumorigenesis","volume":"10","author":"Zhang","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1194\/jlr.RA119000516","article-title":"Metabolic Regulation of the Lysosomal Cofactor Bis(Monoacylglycero)Phosphate in Mice","volume":"61","author":"Grabner","year":"2020","journal-title":"J. Lipid Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.redox.2018.01.013","article-title":"Fasting Exacerbates Hepatic Growth Differentiation Factor 15 to Promote Fatty Acid \u03b2-Oxidation and Ketogenesis via Activating XBP1 Signaling in Liver","volume":"16","author":"Zhang","year":"2018","journal-title":"Redox Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"119023","DOI":"10.1016\/j.lfs.2021.119023","article-title":"Genetic Inhibition of FABP4 Attenuated Endoplasmic Reticulum Stress and Mitochondrial Dysfunction in Rhabdomyolysis-Induced Acute Kidney Injury","volume":"268","author":"Liu","year":"2021","journal-title":"Life Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3258","DOI":"10.1194\/jlr.M034942","article-title":"DHA Attenuates Postprandial Hyperlipidemia via Activating PPAR\u03b1 in Intestinal Epithelial Cells","volume":"54","author":"Kimura","year":"2013","journal-title":"J. Lipid Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"27517","DOI":"10.1038\/srep27517","article-title":"Role of Cystathionine Gamma-Lyase in Immediate Renal Impairment and Inflammatory Response in Acute Ischemic Kidney Injury","volume":"6","author":"Filipovic","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.molmet.2017.03.009","article-title":"FGF21 Resistance Is Not Mediated by Downregulation of Beta-Klotho Expression in White Adipose Tissue","volume":"6","author":"Markan","year":"2017","journal-title":"Mol. Metab."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Stolarczyk, E., Le Gall, M., Even, P., Houllier, A., Serradas, P., Brot-laroche, E., and Leturque, A. (2007). Loss of Sugar Detection by GLUT2 Affects Glucose Homeostasis in Mice. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0001288"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9568269","DOI":"10.1155\/2018\/9568269","article-title":"Effects of Pioglitazone on Nonalcoholic Fatty Liver Disease in the Absence of Constitutive Androstane Receptor Expression","volume":"2018","author":"Ahn","year":"2018","journal-title":"PPAR Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1093\/abbs\/gmaa136","article-title":"AMPK\u03b11 Regulates Idh2 Transcription through H2B O-GlcNAcylation during Brown Adipogenesis","volume":"53","author":"Cao","year":"2021","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1093\/cvr\/cvr028","article-title":"Epigenetic Control of Tissue-Type Plasminogen Activator Synthesis in Human Endothelial Cells","volume":"90","author":"Kruithof","year":"2011","journal-title":"Cardiovasc. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.molmet.2018.03.002","article-title":"Deficiency of Fibroblast Growth Factor 21 (FGF21) Promotes Hepatocellular Carcinoma (HCC) in Mice on a Long Term Obesogenic Diet","volume":"13","author":"Singhal","year":"2018","journal-title":"Mol. Metab."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.2741\/1683","article-title":"Uncoupling protein-2 and non-alcoholic fatty liver disease","volume":"10","author":"Baffy","year":"2005","journal-title":"Front. Biosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3702","DOI":"10.1038\/s41598-018-21939-0","article-title":"Evaluation of Polygenic Determinants of Non-Alcoholic Fatty Liver Disease (NAFLD) By a Candidate Genes Resequencing Strategy","volume":"8","author":"Belardinilli","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"412","DOI":"10.2119\/molmed.2011.00258","article-title":"Glycine N-Methyltransferase Deficiency Affects Niemann-Pick Type C2 Protein Stability and Regulates Hepatic Cholesterol Homeostasis","volume":"18","author":"Liao","year":"2012","journal-title":"Mol. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/j.cmet.2018.01.005","article-title":"An Integrated Understanding of the Rapid Metabolic Benefits of a Carbohydrate-Restricted Diet on Hepatic Steatosis in Humans","volume":"27","author":"Mardinoglu","year":"2018","journal-title":"Cell Metab."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1152\/ajpgi.00079.2013","article-title":"Diet-Induced Mouse Model of Fatty Liver Disease and Nonalcoholic Steatohepatitis Reflecting Clinical Disease Progression and Methods of Assessment","volume":"305","author":"Clapper","year":"2013","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_55","first-page":"12","article-title":"N-Acetylcysteine Improves Liver Function in Patients with Non-Alcoholic Fatty Liver Disease","volume":"10","author":"Khoshbaten","year":"2010","journal-title":"Hepat. Mon."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1038\/ajg.2009.719","article-title":"L-Carnitine Supplementation to Diet: A New Tool in Treatment of Nonalcoholic Steatohepatitis\u2014A Randomized and Controlled Clinical Trial","volume":"105","author":"Malaguarnera","year":"2010","journal-title":"Am. J. Gastroenterol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"109258","DOI":"10.1016\/j.biopha.2019.109258","article-title":"Gypenosides Improve the Intestinal Microbiota of Non-Alcoholic Fatty Liver in Mice and Alleviate Its Progression","volume":"118","author":"Huang","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/mnfr.201600717","article-title":"Sesamol Ameliorates Diet-Induced Obesity in C57BL\/6J Mice and Suppresses Adipogenesis in 3T3-L1 Cells via Regulating Mitochondria-Lipid Metabolism","volume":"61","author":"Liu","year":"2017","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.toxlet.2020.06.020","article-title":"Long-Term Profile of Serological Biomarkers, Hepatic Inflammation, and Fibrosis in a Mouse Model of Non-Alcoholic Fatty Liver Disease","volume":"332","author":"Toita","year":"2020","journal-title":"Toxicol. Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.envres.2015.06.036","article-title":"Adulthood Dietary Exposure to a Common Pesticide Leads to an Obese-like Phenotype and a Diabetic Profile in ApoE3 Mice","volume":"142","author":"Basaure","year":"2015","journal-title":"Environ. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"9396425","DOI":"10.1155\/2017\/9396425","article-title":"Resveratrol and Montelukast Alleviate Paraquat-Induced Hepatic Injury in Mice: Modulation of Oxidative Stress, Inflammation, and Apoptosis","volume":"2017","author":"Abdeltawab","year":"2017","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Choi, S.Y., Park, J.S., Shon, C.H., Lee, C.Y., Ryu, J.M., Son, D.J., Hwang, B.Y., Yoo, H.S., Cho, Y.C., and Lee, J. (2019). Fermented Korean Red Ginseng Extract Enriched in Rd and Rg3 Protects against Non-Alcoholic Fatty Liver Disease through Regulation of MTORC1. Nutrients, 11.","DOI":"10.3390\/nu11122963"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1002\/cbf.1062","article-title":"Protective Effect of Glycine Supplementation on the Levels of Lipid Peroxidation and Antioxidant Enzymes in the Erythrocyte of Rats with Alcohol-Induced Liver Injury","volume":"22","author":"Senthilkumar","year":"2004","journal-title":"Cell Biochem. Funct."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1126\/scitranslmed.aaz2841","article-title":"Glycine-Based Treatment Ameliorates NAFLD by Modulating Fatty Acid Oxidation, Glutathione Synthesis, and the Gut Microbiome","volume":"12","author":"Rom","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1002\/hep.28245","article-title":"Eliciting the Mitochondrial Unfolded Protein Response by Nicotinamide Adenine Dinucleotide Repletion Reverses Fatty Liver Disease in Mice","volume":"63","author":"Gariani","year":"2016","journal-title":"Hepatology"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Zhou, C.C., Yang, X., Hua, X., Liu, J., Fan, M.B., Li, G.Q., Song, J., Xu, T.Y., Li, Z.Y., and Guan, Y.F. (2016). Hepatic NAD+ deficiency as a Therapeutic Target for Non-Alcoholic Fatty Liver Disease in Ageing. Br. J. Pharmacol., 2352\u20132368.","DOI":"10.1111\/bph.13513"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","article-title":"Mechanisms of NAFLD Development and Therapeutic Strategies","volume":"24","author":"Friedman","year":"2018","journal-title":"Nat. Med."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Hernandez-Baixauli, J., Puigb\u00f2, P., Torrell, H., Palacios-Jordan, H., Ripoll, V.J.R., Caimari, A., Bas, J.M.D., Baselga-Escudero, L., and Mulero, M. (2021). A Pilot Study for Metabolic Profiling of Obesity-Associated Microbial Gut Dysbiosis in Male Wistar Rats. Biomolecules, 11.","DOI":"10.3390\/biom11020303"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1152\/ajpgi.00074.2008","article-title":"Gene Expression in Human NAFLD","volume":"294","author":"Greco","year":"2008","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"19034","DOI":"10.1074\/jbc.M115.640292","article-title":"Hyperinsulinemia Enhances Hepatic Expression of the Fatty Acid Transporter Cd36 and Provokes Hepatosteatosis and Hepatic Insulin Resistance","volume":"290","author":"Steneberg","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s12263-012-0300-z","article-title":"Dietary Supplementation with Methyl Donors Reduces Fatty Liver and Modifies the Fatty Acid Synthase DNA Methylation Profile in Rats Fed an Obesogenic Diet","volume":"8","author":"Cordero","year":"2013","journal-title":"Genes Nutr."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.tox.2012.07.007","article-title":"N-Acetylcysteine (NAC) Diminishes the Severity of PCB 126-Induced Fatty Liver in Male Rodents","volume":"302","author":"Lai","year":"2012","journal-title":"Toxicology"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Savic, D., Hodson, L., Neubauer, S., and Pavlides, M. (2020). The Importance of the Fatty Acid Transporter L-Carnitine in Non-Alcoholic Fatty Liver Disease (Nafld). Nutrients, 12.","DOI":"10.3390\/nu12082178"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"G1310","DOI":"10.1152\/ajpgi.00365.2011","article-title":"Hepatic Recruitment of Macrophages Promotes Nonalcoholic Steatohepatitis through CCR2","volume":"302","author":"Miura","year":"2012","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Kitade, H., Chen, G., Ni, Y., and Ota, T. (2017). Nonalcoholic Fatty Liver Disease and Insulin Resistance: New Insights and Potential New Treatments. Nutrients, 9.","DOI":"10.3390\/nu9040387"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"211","DOI":"10.4291\/wjgp.v7.i2.211","article-title":"Insulin Resistance in Development and Progression of Nonalcoholic Fatty Liver Disease","volume":"7","author":"Alam","year":"2016","journal-title":"World J. Gastrointest. Pathophysiol."},{"key":"ref_77","first-page":"1","article-title":"Nicotinamide Riboside Exerts Protective Effect against Aging-Induced NAFLD-like Hepatic Dysfunction in Mice","volume":"2019","author":"Han","year":"2019","journal-title":"PeerJ"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1089\/jmf.2015.3439","article-title":"Nicotinamide Riboside Ameliorates Hepatic Metaflammation by Modulating NLRP3 Inflammasome in a Rodent Model of Type 2 Diabetes","volume":"18","author":"Lee","year":"2015","journal-title":"J. Med. Food"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.cyto.2006.02.006","article-title":"Increased Production of IL-1\u03b1 and TNF-\u03b1 in Lipopolysaccharide-Stimulated Blood from Obese Patients with Non-Alcoholic Fatty Liver Disease","volume":"33","author":"Poniachik","year":"2006","journal-title":"Cytokine"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.ejphar.2015.11.043","article-title":"Betaine Prevented Fructose-Induced NAFLD by Regulating LXR\u03b1\/PPAR\u03b1 Pathway and Alleviating ER Stress in Rats","volume":"770","author":"Ge","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Salic, K., Gart, E., Seidel, F., Verschuren, L., Caspers, M., van Duyvenvoorde, W., Wong, K.E., Keijer, J., Bobeldijk-Pastorova, I., and Wielinga, P.Y. (2019). Combined Treatment with L-Carnitine and Nicotinamide Riboside Improves Hepatic Metabolism and Attenuates Obesity and Liver Steatosis. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184359"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1016\/j.jnutbio.2011.08.004","article-title":"Curcumin Protects against Thioacetamide-Induced Hepatic Fibrosis by Attenuating the Inflammatory Response and Inducing Apoptosis of Damaged Hepatocytes","volume":"23","author":"Wang","year":"2012","journal-title":"J. Nutr. Biochem."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1002\/hep.23639","article-title":"Fatty Liver and Fibrosis in Glycine N-Methyltransferase Knockout Mice Is Prevented by Nicotinamide","volume":"52","author":"Embade","year":"2010","journal-title":"Hepatology"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Werge, M.P., McCann, A., Galsgaard, E.D., Holst, D., Bugge, A., Albrechtsen, N.J.W., and Gluud, L.L. (2021). The Role of the Transsulfuration Pathway in Non-Alcoholic Fatty Liver Disease. J. Clin. Med., 10.","DOI":"10.3390\/jcm10051081"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1007\/s00726-014-1913-x","article-title":"Betaine Supplementation Prevents Fatty Liver Induced by a High-Fat Diet: Effects on One-Carbon Metabolism","volume":"47","author":"Deminice","year":"2015","journal-title":"Amino Acids"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1530\/EC-20-0152","article-title":"Fgf21 Regulates Hepatic Metabolic Pathways to Improve Steatosis and Inflammation","volume":"9","author":"Keinicke","year":"2020","journal-title":"Endocr. Connect."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"147","DOI":"10.3389\/fendo.2015.00147","article-title":"Research Perspectives on the Regulation and Physiological Functions of FGF21 and Its Association with NAFLD","volume":"6","author":"Inagaki","year":"2015","journal-title":"Front. Endocrinol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"30484","DOI":"10.1038\/srep30484","article-title":"Fibroblast Growth Factor 21 Reflects Liver Fat Accumulation and Dysregulation of Signalling Pathways in the Liver of C57BL\/6J Mice","volume":"6","author":"Rusli","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.cmet.2014.06.010","article-title":"The PPAR\u03b1-FGF21 Hormone Axis Contributes to Metabolic Regulation by the Hepatic JNK Signaling Pathway","volume":"20","author":"Vernia","year":"2014","journal-title":"Cell Metab."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"902","DOI":"10.2337\/db15-1094","article-title":"Dietary Betaine Supplementation Increases Fgf21 Levels to Improve Glucose Homeostasis and Reduce Hepatic Lipid Accumulation in Mice","volume":"65","author":"Ejaz","year":"2016","journal-title":"Diabetes"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1007\/s00424-012-1078-y","article-title":"TRPV1 Activation Prevents Nonalcoholic Fatty Liver through UCP2 Upregulation in Mice","volume":"463","author":"Li","year":"2012","journal-title":"Pflug. Arch. Eur. J. Physiol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1136\/gut.2007.147496","article-title":"Uncoupling Protein-2 (UCP2) Induces Mitochondrial Proton Leak and Increases Susceptibility of Non-Alcoholic Steatohepatitis (NASH) Liver to Ischaemia-Reperfusion Injury","volume":"57","author":"Serviddio","year":"2008","journal-title":"Gut"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"5692","DOI":"10.1074\/jbc.274.9.5692","article-title":"Obesity Induces Expression of Uncoupling Protein-2 in Hepatocytes and Promotes Liver ATP Depletion","volume":"274","author":"Chavin","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.redox.2017.11.016","article-title":"Synergistic Interaction of Fatty Acids and Oxysterols Impairs Mitochondrial Function and Limits Liver Adaptation during Nafld Progression","volume":"15","author":"Bellanti","year":"2018","journal-title":"Redox Biol."},{"key":"ref_95","first-page":"1198","article-title":"Protective Effect of Ursodeoxycholic Acid, Resveratrol, and N-Acetylcysteine on Nonalcoholic Fatty Liver Disease in Rats","volume":"54","author":"Ali","year":"2016","journal-title":"Pharm. Biol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1002\/hep.20177","article-title":"Pivotal Role of Superoxide Anion and Beneficial Effect of Antioxidant Molecules in Murine Steatohepatitis","volume":"39","author":"Laurent","year":"2004","journal-title":"Hepatology"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.7150\/ijbs.27173","article-title":"The PI3K\/AKT Pathway in Obesity and Type 2 Diabetes","volume":"14","author":"Huang","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"G1068","DOI":"10.1152\/ajpgi.00249.2010","article-title":"Betaine Improves Nonalcoholic Fatty Liver and Associated Hepatic Insulin Resistance: A Potential Mechanism for Hepatoprotection by Betaine","volume":"299","author":"Kathirvel","year":"2010","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1016\/j.bcp.2012.09.009","article-title":"Piperine, an LXR\u03b1 Antagonist, Protects against Hepatic Steatosis and Improves Insulin Signaling in Mice Fed a High-Fat Diet","volume":"84","author":"Jwa","year":"2012","journal-title":"Biochem. Pharmacol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/j.cmet.2012.03.015","article-title":"Hepatic MTORC2 Activates Glycolysis and Lipogenesis through Akt, Glucokinase, and SREBP1c","volume":"15","author":"Hagiwara","year":"2012","journal-title":"Cell Metab."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1507\/endocrj.K07E-110","article-title":"ChREBP: A Glucose-Activated Transcription Factor Involved in the Development of Metabolic Syndrome","volume":"55","author":"Iizuka","year":"2008","journal-title":"Endocr. J."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1002\/ejlt.201300407","article-title":"Comparative Study of DHA-Enriched Phospholipids and EPA-Enriched Phospholipids on Metabolic Disorders in Diet-Induced-Obese C57BL\/6J Mice","volume":"116","author":"Liu","year":"2014","journal-title":"Eur. J. Lipid Sci. Technol."},{"key":"ref_103","first-page":"196198","article-title":"Crude Extracts from Lycium Barbarum Suppress SREBP-1c Expression and Prevent Diet-Induced Fatty Liver through AMPK Activation","volume":"2014","author":"Li","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2905","DOI":"10.2337\/diabetes.52.12.2905","article-title":"Hepatic Akt Activation Induces Marked Hypoglycemia, Hepatomegaly, and Hypertriglyceridemia with Sterol Regulatory Element Binding Protein Involvement","volume":"52","author":"Ono","year":"2003","journal-title":"Diabetes"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1476-511X-9-25","article-title":"Dietary Saponins of Sea Cucumber Alleviate Orotic Acid-Induced Fatty Liver in Rats via PPAR and SREBP-1c Signaling","volume":"9","author":"Hu","year":"2010","journal-title":"Lipids Health Dis."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"30028","DOI":"10.1074\/jbc.274.42.30028","article-title":"Increased Levels of Nuclear SREBP-1c Associated with Fatty Livers in Two Mouse Models of Diabetes Mellitus *","volume":"274","author":"Shimomura","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.chemosphere.2018.10.058","article-title":"SREBP-1 and LXRA Pathways Mediated Cu-Induced Hepatic Lipid Metabolism in Zebrafish Danio Rerio","volume":"215","author":"Pan","year":"2019","journal-title":"Chemosphere"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.redox.2018.04.006","article-title":"Nicotinamide Riboside Attenuates Alcohol Induced Liver Injuries via Activation of SirT1\/PGC-1\u03b1\/Mitochondrial Biosynthesis Pathway","volume":"17","author":"Wang","year":"2018","journal-title":"Redox Biol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"365","DOI":"10.3389\/fendo.2020.00365","article-title":"The Role of the Pentose Phosphate Pathway in Diabetes and Cancer","volume":"11","author":"Ge","year":"2020","journal-title":"Front Endocrinol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1258\/002367707782314328","article-title":"Impact of \u201cliving Apart Together\u201d on Postoperative Recovery of Mice Compared with Social and Individual Housing","volume":"41","author":"Kuin","year":"2007","journal-title":"Lab. Anim."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.jnutbio.2019.03.005","article-title":"Fish Oil Alleviates Circadian Bile Composition Dysregulation in Male Mice with NAFLD","volume":"69","author":"Liu","year":"2019","journal-title":"J. Nutr. Biochem."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"e1900358","DOI":"10.1002\/mnfr.201900358","article-title":"Maresin 1 Regulates Hepatic FGF21 in Diet-Induced Obese Mice and in Cultured Hepatocytes","volume":"63","author":"Laiglesia","year":"2019","journal-title":"Mol. Nutr. Food Res."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/10\/3532\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:10:45Z","timestamp":1760166645000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/10\/3532"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,9]]},"references-count":112,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["nu13103532"],"URL":"https:\/\/doi.org\/10.3390\/nu13103532","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,9]]}}}