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Recent studies have revealed that histone regulation of key genes for lipogenesis and adipogenesis in the liver is one of the crucial mechanisms for olanzapine-induced metabolic disorders. This study investigated the role of epigenetic histone regulation in betahistine co-treatment preventing dyslipidemia and fatty liver caused by chronic olanzapine treatment in a rat model. In addition to abnormal lipid metabolism, the upregulation of peroxisome proliferator-activated receptor \u03b3 (PPAR\u03b3) and CCAAT\/enhancer binding protein (C\/EBP\u03b1), as well as the downregulation of carnitine palmitoyltransferase 1A (CPT1A) in the liver induced by olanzapine, were significantly attenuated by betahistine co-treatment. In addition, betahistine co-treatment significantly enhanced the global expression of H3K4me and the enrichment of H3K4me binding on the promoter of Cpt1a gene as revealed by ChIP-qPCR, but inhibited the expression of one of its site-specific demethylases, lysine (K)-specific demethylase 1A (KDM1A). Betahistine co-treatment also significantly enhanced the global expression of H3K9me and the enrichment of H3K9me binding on the promoter of the Pparg gene, but inhibited the expression of two of its site-specific demethylases, lysine demethylase 4B (KDM4B) and PHD finger protein 2 (PHF2). These results suggest that betahistine attenuates abnormal adipogenesis and lipogenesis triggered by olanzapine through modulating hepatic histone methylation, and thus inhibiting the PPAR\u03b3 pathway-mediated lipid storage, while at the same time promoting CP1A-mediated fatty acid oxidation.<\/jats:p>","DOI":"10.3390\/ijms24119143","type":"journal-article","created":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T08:14:28Z","timestamp":1684829668000},"page":"9143","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Epigenetic Histone Methylation of PPAR\u03b3 and CPT1A Signaling Contributes to Betahistine Preventing Olanzapine-Induced Dyslipidemia"],"prefix":"10.3390","volume":"24","author":[{"given":"Yueqing","family":"Su","sequence":"first","affiliation":[{"name":"Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynaecology and Paediatrics, Fujian Medical University, Fuzhou 350005, China"},{"name":"Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia"},{"name":"School of Medical, Indigenous and Health Sciences, and Molecular Horizons, University of Wollongong, Wollongong, NSW 2522, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1147-5741","authenticated-orcid":false,"given":"Chao","family":"Deng","sequence":"additional","affiliation":[{"name":"Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia"},{"name":"School of Medical, Indigenous and Health Sciences, and Molecular Horizons, University of Wollongong, Wollongong, NSW 2522, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Medical Research Institute, Southwest University, Chongqing 400716, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiamei","family":"Lian","sequence":"additional","affiliation":[{"name":"Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia"},{"name":"School of Medical, Indigenous and Health Sciences, and Molecular Horizons, University of Wollongong, Wollongong, NSW 2522, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,23]]},"reference":[{"key":"ref_1","first-page":"666","article-title":"Olanzapine","volume":"71","author":"Nagai","year":"2013","journal-title":"Nihon Rinsho"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1007\/s40264-017-0543-0","article-title":"Second-Generation Antipsychotics and Metabolic Side Effects: A Systematic Review of Population-Based Studies","volume":"40","author":"Hirsch","year":"2017","journal-title":"Drug Saf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.ecl.2013.05.006","article-title":"Effects of antipsychotic medications on appetite, weight, and insulin resistance","volume":"42","author":"Deng","year":"2013","journal-title":"Endocrinol. 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