{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T16:47:44Z","timestamp":1789663664343,"version":"4.0.1"},"reference-count":51,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,2,23]],"date-time":"2024-02-23T00:00:00Z","timestamp":1708646400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["201906210058"],"award-info":[{"award-number":["201906210058"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing healthcare problem with limited therapeutic options. Progress in this field depends on the availability of reliable preclinical models. Human precision-cut liver slices (PCLSs) have been employed to replicate the initiation of MASLD, but a comprehensive investigation into MASLD progression is still missing. This study aimed to extend the current incubation time of human PCLSs to examine different stages in MASLD. Healthy human PCLSs were cultured for up to 96 h in a medium enriched with high sugar, high insulin, and high fatty acids to induce MASLD. PCLSs displayed hepatic steatosis, characterized by accumulated intracellular fat. The development of hepatic steatosis appeared to involve a time-dependent impact on lipid metabolism, with an initial increase in fatty acid uptake and storage, and a subsequent down-regulation of lipid oxidation and secretion. PCLSs also demonstrated liver inflammation, including increased pro-inflammatory gene expression and cytokine production. Additionally, liver fibrosis was also observed through the elevated production of pro-collagen 1a1 and tissue inhibitor of metalloproteinase-1 (TIMP1). RNA sequencing showed that the tumor necrosis factor alpha (TNF\u03b1) signaling pathway and transforming growth factor beta (TGF\u03b2) signaling pathway were consistently activated, potentially contributing to the development of inflammation and fibrosis. In conclusion, the prolonged incubation of human PCLSs can establish a robust ex vivo model for MASLD, facilitating the identification and evaluation of potential therapeutic interventions.<\/jats:p>","DOI":"10.3390\/nu16050626","type":"journal-article","created":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T08:59:01Z","timestamp":1708937941000},"page":"626","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Metabolic Dysfunction-Associated Steatotic Liver Disease in a Dish: Human Precision-Cut Liver Slices as a Platform for Drug Screening and Interventions"],"prefix":"10.3390","volume":"16","author":[{"given":"Mei","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik T.","family":"Larsen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marius C.","family":"van den Heuvel","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology, Pathology Section, University Medical Center Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstanze","family":"Gier","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan R.","family":"Gorter","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorenda","family":"Oosterhuis","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0375-4460","authenticated-orcid":false,"given":"Johan","family":"Bijzet","sequence":"additional","affiliation":[{"name":"Amyloidosis Center of Expertise, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands"},{"name":"Department of Laboratory Medicine, Division of Medical Immunology, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7900-5917","authenticated-orcid":false,"given":"Vincent E.","family":"de Meijer","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5322-3887","authenticated-orcid":false,"given":"Kim","family":"Ravnskjaer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7541-588X","authenticated-orcid":false,"given":"Anika","family":"Nagelkerke","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Analysis, Groningen Research Institute of Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4855-8452","authenticated-orcid":false,"given":"Peter","family":"Olinga","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S32","DOI":"10.3350\/cmh.2022.0365","article-title":"Global incidence and prevalence of nonalcoholic fatty liver disease","volume":"29","author":"Teng","year":"2023","journal-title":"Clin. 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