{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T20:15:17Z","timestamp":1793823317046,"version":"4.6.1"},"reference-count":164,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,11,14]],"date-time":"2023-11-14T00:00:00Z","timestamp":1699920000000},"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":["200110"],"award-info":[{"award-number":["200110"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>The central mechanism involved in the pathogenesis of MAFLD is insulin resistance with hyperinsulinemia, which stimulates triglyceride synthesis and accumulation in the liver. On the other side, triglyceride and free fatty acid accumulation in hepatocytes promotes insulin resistance via oxidative stress, endoplasmic reticulum stress, lipotoxicity, and the increased secretion of hepatokines. Cytokines and adipokines cause insulin resistance, thus promoting lipolysis in adipose tissue and ectopic fat deposition in the muscles and liver. Free fatty acids along with cytokines and adipokines contribute to insulin resistance in the liver via the activation of numerous signaling pathways. The secretion of hepatokines, hormone-like proteins, primarily by hepatocytes is disturbed and impairs signaling pathways, causing metabolic dysregulation in the liver. ER stress and unfolded protein response play significant roles in insulin resistance aggravation through the activation of apoptosis, inflammatory response, and insulin signaling impairment mediated via IRE1\/PERK\/ATF6 signaling pathways and the upregulation of SREBP 1c. Circadian rhythm derangement and biological clock desynchronization are related to metabolic disorders, insulin resistance, and NAFLD, suggesting clock genes as a potential target for new therapeutic strategies. This review aims to summarize the mechanisms of hepatic insulin resistance involved in NAFLD development and progression.<\/jats:p>","DOI":"10.3390\/cimb45110570","type":"journal-article","created":{"date-parts":[[2023,11,14]],"date-time":"2023-11-14T11:04:32Z","timestamp":1699959872000},"page":"9084-9102","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":97,"title":["The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease\u2014The Transition from an Adipocentric to Liver-Centric Approach"],"prefix":"10.3390","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7505-5466","authenticated-orcid":false,"given":"Milena","family":"Veskovi\u0107","sequence":"first","affiliation":[{"name":"Institute of Pathophysiology \u201cLjubodrag Buba Mihailovic\u201d, Faculty of Medicine, University of Belgrade, 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 \u201cRichard Burian\u201d, Faculty of Medicine, University of Belgrade, 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 \u201cRichard Burian\u201d, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5317-3827","authenticated-orcid":false,"given":"Olivera","family":"Stanojlovi\u0107","sequence":"additional","affiliation":[{"name":"Institute of Medical Physiology \u201cRichard Burian\u201d, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6731-8596","authenticated-orcid":false,"given":"Djuro","family":"Macut","sequence":"additional","affiliation":[{"name":"Clinic of Endocrinology, Diabetes and Metabolic Diseases, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Du\u0161an","family":"Mladenovi\u0107","sequence":"additional","affiliation":[{"name":"Institute of Pathophysiology \u201cLjubodrag Buba Mihailovic\u201d, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e218","DOI":"10.1038\/emm.2015.122","article-title":"Regulation of glucose metabolism from a liver-centric perspective","volume":"48","author":"Han","year":"2016","journal-title":"Exp. 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