{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T03:19:33Z","timestamp":1787973573010,"version":"build-2784847793"},"reference-count":117,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2024,7,5]],"date-time":"2024-07-05T00:00:00Z","timestamp":1720137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science Technological Development and Innovation of the Republic of Serbia","award":["451-03-66\/2024-03\/200110"],"award-info":[{"award-number":["451-03-66\/2024-03\/200110"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>While obesity-related nonalcoholic fatty liver disease (NAFLD) is linked with metabolic dysfunctions such as insulin resistance and adipose tissue inflammation, lean NAFLD more often progresses to liver fibrosis even in the absence of metabolic syndrome. This review aims to summarize the current knowledge regarding the mechanisms of liver fibrosis in lean NAFLD. The most commonly used lean NAFLD models include a methionine\/choline-deficient (MCD) diet, a high-fat diet with carbon tetrachloride (CCl4), and a high-fructose and high-cholesterol diet. The major pro-fibrogenic mechanisms in lean NAFLD models include increased activation of the extracellular signal-regulated kinase (ERK) pathway, elevated expression of \u03b1-smooth muscle actin (\u03b1-SMA), collagen type I, and TGF-\u03b2, and modulation of fibrogenic markers such as tenascin-X and metalloproteinase inhibitors. Additionally, activation of macrophage signaling pathways promoting hepatic stellate cell (HSC) activation further contributes to fibrosis development. Animal models cannot cover all clinical features that are evident in patients with lean or obese NAFLD, implicating the need for novel models, as well as for deeper comparisons of clinical and experimental studies. Having in mind the prevalence of fibrosis in lean NAFLD patients, by addressing specific pathways, clinical studies can reveal new targeted therapies along with novel biomarkers for early detection and enhancement of clinical management for lean NAFLD patients.<\/jats:p>","DOI":"10.3390\/ijms25137405","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T12:21:03Z","timestamp":1720441263000},"page":"7405","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Exploring Fibrosis Pathophysiology in Lean and Obese Metabolic-Associated Fatty Liver Disease: An In-Depth Comparison"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7505-5466","authenticated-orcid":false,"given":"Milena","family":"Veskovi\u0107","sequence":"first","affiliation":[{"name":"Institute of Pathophysiology, Faculty of Medicine, University of Belgrade, Dr Suboti\u0107a 9, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milka","family":"Pejovi\u0107","sequence":"additional","affiliation":[{"name":"Primary Health Center \u201cVra\u010dar\u201d, Velimira Bate \u017divojinovi\u0107a 16, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9499-3247","authenticated-orcid":false,"given":"Nikola","family":"\u0160utulovi\u0107","sequence":"additional","affiliation":[{"name":"Institute of Medical Physiology, Faculty of Medicine, University of Belgrade, Vi\u0161egradska 26, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0806-444X","authenticated-orcid":false,"given":"Dragan","family":"Hrn\u010di\u0107","sequence":"additional","affiliation":[{"name":"Institute of Medical Physiology, Faculty of Medicine, University of Belgrade, Vi\u0161egradska 26, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Ra\u0161i\u0107-Markovi\u0107","sequence":"additional","affiliation":[{"name":"Institute of Medical Physiology, Faculty of Medicine, University of Belgrade, Vi\u0161egradska 26, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivera","family":"Stanojlovi\u0107","sequence":"additional","affiliation":[{"name":"Institute of Medical Physiology, Faculty of Medicine, University of Belgrade, Vi\u0161egradska 26, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8921-6232","authenticated-orcid":false,"given":"Du\u0161an","family":"Mladenovi\u0107","sequence":"additional","affiliation":[{"name":"Institute of Pathophysiology, Faculty of Medicine, University of Belgrade, Dr Suboti\u0107a 9, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"329","DOI":"10.14218\/JCTH.2021.00178","article-title":"Metabolic-associated Fatty Liver Disease (MAFLD): A Multi-systemic Disease Beyond the Liver","volume":"10","author":"Kaya","year":"2022","journal-title":"J. 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