{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T22:37:54Z","timestamp":1790116674096,"version":"4.0.1"},"reference-count":35,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T00:00:00Z","timestamp":1727308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bando Ricerca UPO 2022","award":["MUR-DM 737\/2021"],"award-info":[{"award-number":["MUR-DM 737\/2021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Methyltransferase EZH2-mediated H3K27me3 is involved in liver inflammation and fibrosis, but its role in hepatic metabolic derangements is not yet clearly defined. We investigated if a high-fat diet (HFD) induced early changes in EZH2 expression and H3K27 me3 in the liver of mice. Methods: Five-week-old mice were fed an HFD or a low-fat diet (Control) for 2 weeks (2 W) or 8 weeks (8 W). Body weight was recorded weekly. Glycemia and oral glucose tolerance were assessed at baseline and after 2 W\u20138 W. Finally, livers were collected for further analysis. Results: As expected, mice that received 8 W HFD showed an increase in body weight, glycemia, and liver steatosis and an impairment in glucose tolerance; no alterations were observed in 2 W HFD mice. Eight weeks of HFD caused hepatic EZH2 nuclear localization and increased H3 K27me3; surprisingly, the same alterations occurred in 2 W HFD mice livers, even before overweight onset. We demonstrated that selective EZH2 inhibition reduced H3K27me3 and counteracted lipid accumulation in HUH-7 cells upon palmitic acid treatment. Conclusions: In conclusion, we point to EZH2\/H3K27me3 as an early epigenetic event occurring in fatty-acid-challenged livers both in vivo and in vitro, thus establishing EZH2 as a potential pharmacological target for metabolic derangements.<\/jats:p>","DOI":"10.3390\/nu16193260","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T11:40:27Z","timestamp":1727350827000},"page":"3260","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["EZH2-Mediated H3K27 Trimethylation in the Liver of Mice Is an Early Epigenetic Event Induced by High-Fat Diet Exposure"],"prefix":"10.3390","volume":"16","author":[{"given":"Giulia","family":"Pinton","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universit\u00e0 del Piemonte Orientale (UPO), Largo Donegani 2, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattia","family":"Perucca","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universit\u00e0 del Piemonte Orientale (UPO), Largo Donegani 2, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Gigliotti","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universit\u00e0 del Piemonte Orientale (UPO), Largo Donegani 2, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Mantovani","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universit\u00e0 del Piemonte Orientale (UPO), Largo Donegani 2, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nausicaa","family":"Clemente","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Universit\u00e0 del Piemonte Orientale (UPO), Via Solaroli 17, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1950-3364","authenticated-orcid":false,"given":"Justyna","family":"Malecka","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universit\u00e0 del Piemonte Orientale (UPO), Largo Donegani 2, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5235-1561","authenticated-orcid":false,"given":"Gabriela","family":"Chrostek","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universit\u00e0 del Piemonte Orientale (UPO), Largo Donegani 2, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6317-3182","authenticated-orcid":false,"given":"Giulia","family":"Dematteis","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universit\u00e0 del Piemonte Orientale (UPO), Largo Donegani 2, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4316-2654","authenticated-orcid":false,"given":"Dmitry","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universit\u00e0 del Piemonte Orientale (UPO), Largo Donegani 2, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Moro","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universit\u00e0 del Piemonte Orientale (UPO), Largo Donegani 2, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7273-0051","authenticated-orcid":false,"given":"Fausto","family":"Chiazza","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Universit\u00e0 del Piemonte Orientale (UPO), Largo Donegani 2, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1080\/21623945.2015.1071454","article-title":"A Short Bout of HFD Promotes Long-Lasting Hepatic Lipid Accumulation","volume":"5","author":"Chiazza","year":"2016","journal-title":"Adipocyte"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1124\/jpet.116.235069","article-title":"Empagliflozin Protects against Diet-Induced NLRP-3 Inflammasome Activation and Lipid Accumulation","volume":"359","author":"Benetti","year":"2016","journal-title":"J. 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