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As exposure is demonstrated to cause nonalcoholic fatty liver disease (NAFLD), and the underlying epigenetic mechanisms remain largely unknown. This study aimed to investigate the roles of histone modifications in low-level As exposure-induced NAFLD in rats. The results showed that exposure to As caused lipid accumulation and upregulated the expression of lipid metabolism-related genes Fabp1, Srebf1, and Apoc3, while downregulated Acox1 and Cpt1a in rat liver. In addition, it was found that inorganic arsenite (iAsIII) was methylated to DMA, and the S-adenosylmethionine (SAM) level was decreased, which would contribute to the repression of H3K9me1\/2 in rat liver after exposure. The in vitro studies revealed that SAM supplementation attenuated lipid accumulation by restoring H3K9me1\/2 in HepG2 cells, which further confirmed our animal results. Therefore, it is suggested that As methylation depleted SAM, which inhibited H3K9me1\/2 and activated Fabp1, Srebf1, and Apoc3 expressions, leading to NAFLD upon inorganic As exposure. Overall, these data shed new light on the role of SAM-mediated histone methylation in As-triggered NAFLD, which could be useful for the prevention and intervention of hepatotoxicity induced by environmental As exposure.<\/jats:p>","DOI":"10.1021\/acs.est.4c10417","type":"journal-article","created":{"date-parts":[[2025,1,2]],"date-time":"2025-01-02T21:04:51Z","timestamp":1735851891000},"page":"268-278","source":"Crossref","is-referenced-by-count":12,"title":["Arsenic\nExposure\nTriggers Nonalcoholic Fatty Liver\nDisease through Repressing\n                    <i>S<\/i>\n                    \u2011Adenosylmethionine-Dependent\nHistone Methylation in Rats"],"prefix":"10.1021","volume":"59","author":[{"given":"Lu","family":"Lu","sequence":"first","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Xiamen, China, 361021"]},{"name":"Fujian Agriculture and Forestry University , , ,","place":["Fuzhou, China, 350002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weizhen","family":"Hua","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Xiamen, China, 361021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuping","family":"Li","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Xiamen, China, 361021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenbin","family":"Che","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Xiamen, China, 361021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9354-803X","authenticated-orcid":true,"given":"Meiping","family":"Tian","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Xiamen, China, 361021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Yang","family":"Lu","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Xiamen, China, 361021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaoqiao","family":"Chi","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Xiamen, China, 361021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9732-798X","authenticated-orcid":true,"given":"Jie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Xiamen University , , ,","place":["Xiamen, China, 361102"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5076-2084","authenticated-orcid":true,"given":"Qingyu","family":"Huang","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Xiamen, China, 361021"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2025,1,2]]},"reference":[{"key":"2026081210104964100_cit1","doi-asserted-by":"publisher","first-page":"5777","DOI":"10.1016\/j.watres.2010.06.021","article-title":"Health risk assessment\nof inorganic arsenic intake of Cambodia residents through groundwater\ndrinking pathway","volume":"44","author":"Phan","year":"2010","journal-title":"Water Res."},{"key":"2026081210104964100_cit2","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1007\/s12199-011-0247-5","article-title":"Arsenic speciation analysis of urine\nsamples from individuals living\nin an arsenic-contaminated area in Bangladesh","volume":"17","author":"Hata","year":"2012","journal-title":"Environ. 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