{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T10:26:22Z","timestamp":1790331982979,"version":"4.1.0"},"reference-count":47,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2019,10,29]],"date-time":"2019-10-29T00:00:00Z","timestamp":1572307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Insulin resistance (IR) and microRNAs (miRNAs), which regulate cell-to-cell communication between hepatocytes and hepatic stellate cells (HSCs), may intertwine in nonalcoholic fatty liver disease (NAFLD) pathogenesis. The aim of this study was to evaluate whether epigenetics and environmental factors interact to promote progressive NAFLD during IR. We examined the miRNA signature in insulin receptor haploinsufficient (InsR+\/\u2212) and wild-type (wt) HSCs by RNAseq (n = 4 per group). Then, we evaluated their impact in an IR-NASH (nonalcoholic steatohepatitis) model (InsR+\/\u2212 mice fed standard or methionine choline deficient (MCD) diet, n = 10 per group) and in vitro. InsR+\/\u2212 HSCs displayed 36 differentially expressed miRNAs (p &lt; 0.05 vs. wt), whose expression was then analyzed in the liver of InsR+\/\u2212 mice fed an MCD diet. We found that miR-101-3p negatively associated with both InsR+\/\u2212 genotype and MCD (p &lt; 0.05) and the histological spectrum of liver damage (p &lt; 0.01). miR-101-3p was reduced in InsR+\/\u2212 hepatocytes and HSCs and even more in InsR+\/\u2212 cells exposed to insulin (0.33 \u00b5M) and fatty acids (0.25 mM), resembling the IR-NASH model. Conversely, insulin induced miR-101-3p expression in wt cells but not in InsR+\/\u2212 ones (p &lt; 0.05). In conclusion, IR combined with diet-induced liver injury favors miR-101-3p downregulation, which may promote progressive NAFLD through HSC and hepatocyte transdifferentiation and proliferation.<\/jats:p>","DOI":"10.3390\/nu11112597","type":"journal-article","created":{"date-parts":[[2019,10,31]],"date-time":"2019-10-31T05:18:26Z","timestamp":1572499106000},"page":"2597","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["mir-101-3p Downregulation Promotes Fibrogenesis by Facilitating Hepatic Stellate Cell Transdifferentiation During Insulin Resistance"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4161-4178","authenticated-orcid":false,"given":"Marica","family":"Meroni","sequence":"first","affiliation":[{"name":"General Medicine and Metabolic Diseases, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Milano 20122, Italy"},{"name":"Department of Pathophysiology and Transplantation, Universit\u00e0 degli Studi di Milano, Milano 20122, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9433-3492","authenticated-orcid":false,"given":"Miriam","family":"Longo","sequence":"additional","affiliation":[{"name":"General Medicine and Metabolic Diseases, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Milano 20122, Italy"},{"name":"Department of Clinical Sciences and Community Health, Universit\u00e0 degli Studi di Milano, Milano 20122, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Erconi","sequence":"additional","affiliation":[{"name":"General Medicine and Metabolic Diseases, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Milano 20122, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8909-0345","authenticated-orcid":false,"given":"Luca","family":"Valenti","sequence":"additional","affiliation":[{"name":"Transfusional Center\u2013Translational Medicine, Fondazione IRCCS C\u00e0 Granda Ospedale Maggiore Policlinico Milano, Milano 20122, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Gatti","sequence":"additional","affiliation":[{"name":"Preclinical Research Center, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Milano 20122, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Ludovica","family":"Fracanzani","sequence":"additional","affiliation":[{"name":"General Medicine and Metabolic Diseases, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Milano 20122, Italy"},{"name":"Department of Pathophysiology and Transplantation, Universit\u00e0 degli Studi di Milano, Milano 20122, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4343-7213","authenticated-orcid":false,"given":"Paola","family":"Dongiovanni","sequence":"additional","affiliation":[{"name":"General Medicine and Metabolic Diseases, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Milano 20122, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1053\/j.gastro.2005.11.017","article-title":"From fat to inflammation","volume":"130","author":"Day","year":"2006","journal-title":"Gastroenterology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1053\/j.gastro.2014.11.039","article-title":"Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States","volume":"148","author":"Wong","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Dongiovanni, P., Meroni, M., Longo, M., Fargion, S., and Fracanzani, A.L. 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