{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T10:57:13Z","timestamp":1781780233168,"version":"3.54.5"},"reference-count":37,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Regenerative medicine integrates interdisciplinary approaches towards restoring the function of diseased organs. This study examined alterations that occurred in the liver under a high-fat diet (HFD) with the development of obesity and fatty liver, and changes in metabolic homeostasis and glucose levels, in mice. HFD nutrition causes hyperglycemia, leading to the formation and accumulation of advanced glycation end-products (AGEs) promoting protein post-translational modifications (PTMs) and introducing crosslinking in the extracellular matrix (ECM). Using histological and gene expression analyses, we detected an increase in adiposity, as well as in ECM protein deposition in the liver. Further, decellularization of the liver yielded the isolated ECM organ scaffold, allowing us to analyze the chemical modification in proteins by various imaging methods combined with spectroscopy. The measurements of intrinsic protein fluorescence are consistent with increased AGE-associated levels. SEM allows for the visualization of ECM fiber thickening as a result of protein crosslinking. Using cathodoluminescence, a label-free imaging method, we confirmed the protein modifications. The combination of innovative technologies highlights the ECM structural alterations associated with impaired glucose regulation and liver adiposity. These findings provide novel views on liver-scaffold ECM structure under metabolic diseases that will play a significant role in accelerating the understanding of effective regenerative therapies.<\/jats:p>","DOI":"10.3390\/cells15121105","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T10:25:34Z","timestamp":1781778334000},"page":"1105","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["High-Fat-Diet-Induced Hyperglycemia Alters Liver Extracellular Matrix Composition in Mice Model"],"prefix":"10.3390","volume":"15","author":[{"given":"Roza","family":"Izgilov","sequence":"first","affiliation":[{"name":"Department of Cell and Developmental Biology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0397-5388","authenticated-orcid":false,"given":"Nahum","family":"Kavin","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4566-5667","authenticated-orcid":false,"given":"Omri","family":"Ofek","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadav","family":"Kislev","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1522-1362","authenticated-orcid":false,"given":"Dafna","family":"Benayahu","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1016\/j.apsb.2025.02.007","article-title":"Post-translational modifications of collagen and its related diseases in metabolic pathways","volume":"15","author":"Guo","year":"2025","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10198","DOI":"10.1021\/jf305117s","article-title":"Fragmentation pathways during maillard-induced carbohydrate degradation","volume":"61","author":"Smuda","year":"2013","journal-title":"J. Agric. Food Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.2337\/diabetes.54.6.1615","article-title":"The pathobiology of diabetic complications: A unifying mechanism","volume":"54","author":"Brownlee","year":"2005","journal-title":"Diabetes"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1172\/JCI119885","article-title":"Overexpression of glyoxalase-I in bovine endothelial cells inhibits intracellular advanced glycation endproduct formation and prevents hyperglycemia-induced increases in macromolecular endocytosis","volume":"101","author":"Shinohara","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.cmet.2018.08.014","article-title":"The Role of Advanced Glycation End Products in Aging and Metabolic Diseases: Bridging Association and Causality","volume":"28","author":"Chaudhuri","year":"2018","journal-title":"Cell Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.biochi.2010.12.003","article-title":"The glycation of albumin: Structural and functional impacts","volume":"93","author":"Rondeau","year":"2011","journal-title":"Biochimie"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4196\/kjpp.2014.18.1.1","article-title":"Advanced glycation end products and diabetic complications","volume":"18","author":"Singh","year":"2014","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1007\/s00018-010-0263-4","article-title":"Adipocyte extracellular matrix composition, dynamics and role in obesity","volume":"67","author":"Mariman","year":"2010","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"111315","DOI":"10.1016\/j.biopha.2021.111315","article-title":"Adipose tissue and insulin resistance in obese","volume":"137","author":"Ahmed","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.bcp.2016.05.005","article-title":"Adipose extracellular matrix remodelling in obesity and insulin resistance","volume":"119","author":"Lin","year":"2016","journal-title":"Biochem. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"27398","DOI":"10.1038\/srep27398","article-title":"The alterations in the extracellular matrix composition guide the repair of damaged liver tissue","volume":"6","author":"Klaas","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"12411","DOI":"10.1038\/s41598-025-97670-4","article-title":"Machine learning-based integration reveals reliable biomarkers and potential mechanisms of NASH progression to fibrosis","volume":"15","author":"Feng","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"109199","DOI":"10.1016\/j.cbi.2020.109199","article-title":"High fat diet-triggered non-alcoholic fatty liver disease: A review of proposed mechanisms","volume":"330","author":"Lian","year":"2020","journal-title":"Chem. Biol. Interact."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Twarda-clapa, A., Olczak, A., Bia\u0142kowska, A.M., and Kozio\u0142kiewicz, M. (2022). Advanced Glycation End-Products (AGEs): Formation, Chemistry, Classification, Receptors, and Diseases Related to AGEs. Cells, 11.","DOI":"10.3390\/cells11081312"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"19846","DOI":"10.3390\/ijms141019846","article-title":"Development of nonalcoholic hepatopathy: Contributions of oxidative stress and advanced glycation end products","volume":"14","author":"Santos","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Naftaly, A., Kislev, N., Izgilov, R., Adler, R., Silber, M., Shalgi, R., and Benayahu, D. (2022). Nutrition Alters the Stiffness of Adipose Tissue and Cell Signaling. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232315237"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"156028","DOI":"10.1016\/j.metabol.2024.156028","article-title":"The role of dietary modification in the prevention and management of metabolic dysfunction-associated fatty liver disease: An international multidisciplinary expert consensus","volume":"161","author":"Zeng","year":"2024","journal-title":"Metabolism"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2212\u0394\u0394CT Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and validation of a histological scoring system for nonalcoholic fatty liver disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1002\/hep.24067","article-title":"The use of whole organ decellularization for the generation of a vascularized liver organoid","volume":"53","author":"Baptista","year":"2011","journal-title":"Hepatology"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kislev, N., Izgilov, R., Adler, R., and Benayahu, D. (2021). Exploring the cell stemness and the complexity of the adipose tissue niche. Biomolecules, 11.","DOI":"10.3390\/biom11121906"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1093\/jn\/nxz017","article-title":"Dietary genistein inhibits methylglyoxal-induced advanced glycation end product formation in mice fed a high-fat diet","volume":"149","author":"Zhao","year":"2019","journal-title":"J. Nutr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1111\/jgh.12042","article-title":"Advanced glycation end products augment experimental hepatic fibrosis","volume":"28","author":"Goodwin","year":"2013","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1177\/1932296820965259","article-title":"Diabetes Status is Associated With Plantar Soft Tissue Stiffness Measured Using Ultrasound Reverberant Shear Wave Elastography Approach","volume":"16","author":"Naemi","year":"2022","journal-title":"J. Diabetes Sci. Technol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"eabo1673","DOI":"10.1126\/sciadv.abo1673","article-title":"Diabetic hyperglycemia promotes primary tumor progression through glycation-induced tumor extracellular matrix stiffening","volume":"8","author":"Wang","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1038\/s41586-023-06991-9","article-title":"Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver","volume":"626","author":"Fan","year":"2024","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Izgilov, R., Naftaly, A., and Benayahu, D. (2023). Advanced Glycation End Products Effects on Adipocyte Niche Stiffness and Cell Signaling. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032261"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1111\/j.1749-6632.2011.06320.x","article-title":"Receptor for AGE (RAGE): Signaling mechanisms in the pathogenesis of diabetes and its complications","volume":"1243","author":"Ramasamy","year":"2011","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1007\/s00592-015-0763-7","article-title":"Advanced glycation end product (AGE)-induced hepatic stellate cell activation via autophagy contributes to hepatitis C-related fibrosis","volume":"52","author":"He","year":"2015","journal-title":"Acta Diabetol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4798","DOI":"10.1038\/s41598-025-89433-y","article-title":"Advanced glycation end products and risk of mortality in patients with cirrhosis: A prospective cohort study","volume":"15","author":"Tabar","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3179","DOI":"10.1021\/acsbiomaterials.1c00387","article-title":"Revealing Advanced Glycation End Products Associated Structural Changes in Serum Albumin","volume":"7","author":"Naftaly","year":"2021","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4913","DOI":"10.3748\/wjg.v27.i29.4913","article-title":"Advanced glycation end product: A potential biomarker for risk stratification of non-alcoholic fatty liver disease in ELSA-Brasil study","volume":"27","author":"Pereira","year":"2021","journal-title":"World J. Gastroenterol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/s42003-019-0313-x","article-title":"Quantitative intrinsic auto-cathodoluminescence can resolve spectral signatures of tissue-isolated collagen extracellular matrix","volume":"2","author":"Zielinski","year":"2019","journal-title":"Commun. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3346","DOI":"10.1073\/pnas.0400088101","article-title":"Scanning electron microscopy of cells and tissues under fully hydrated conditions","volume":"101","author":"Thiberge","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e2304288120","DOI":"10.1073\/pnas.2304288120","article-title":"Defined extracellular matrix compositions support stiffness- insensitive cell spreading and adhesion signaling","volume":"120","author":"Conway","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fphys.2023.1098129","article-title":"Regulators, functions, and mechanotransduction pathways of matrix stiffness in hepatic disease","volume":"14","author":"Guo","year":"2023","journal-title":"Front. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1038\/s41551-023-01019-z","article-title":"Advanced glycation end-products as mediators of the aberrant crosslinking of extracellular matrix in scarred liver tissue","volume":"7","author":"Lyu","year":"2023","journal-title":"Nat. Biomed. Eng."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/12\/1105\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T10:42:15Z","timestamp":1781779335000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/12\/1105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,18]]},"references-count":37,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["cells15121105"],"URL":"https:\/\/doi.org\/10.3390\/cells15121105","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,18]]}}}