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DNA methylation is an epigenetic link between environmental factors (e.g., diets) and complex diseases (e.g., non\u2010alcoholic fatty liver disease). Here, it is aimed to study the role of DNA methylation in the regulation of hepatic lipid metabolism. A dynamic change in the DNA methylome in the liver of high\u2010fat diet (HFD)\u2010fed mice is discovered, including a marked increase in DNA methylation at the promoter of Beta\u2010klotho (<jats:italic>Klb)<\/jats:italic>, a co\u2010receptor for the biological functions of fibroblast growth factor (FGF)15\/19 and FGF21. DNA methyltransferases (DNMT) 1 and 3A mediate HFD\u2010induced methylation at the <jats:italic>Klb<\/jats:italic> promoter. Notably, HFD enhances DNMT1 protein stability via a ubiquitination\u2010mediated mechanism. Liver\u2010specific deletion of <jats:italic>Dnmt1<\/jats:italic> or <jats:italic>3a<\/jats:italic> increases <jats:italic>Klb<\/jats:italic> expression and ameliorates HFD\u2010induced hepatic steatosis. Single\u2010nucleus RNA sequencing analysis reveals pathways involved in fatty acid oxidation in <jats:italic>Dnmt1<\/jats:italic>\u2010deficient hepatocytes. Targeted demethylation at the <jats:italic>Klb<\/jats:italic> promoter increases <jats:italic>Klb<\/jats:italic> expression and fatty acid oxidation, resulting in decreased hepatic lipid accumulation. Up\u2010regulation of methyltransferases by HFD may induce hypermethylation of the <jats:italic>Klb<\/jats:italic> promoter and subsequent down\u2010regulation of <jats:italic>Klb<\/jats:italic> expression, resulting in the development of hepatic steatosis.<\/jats:p>","DOI":"10.1002\/advs.202206068","type":"journal-article","created":{"date-parts":[[2023,6,7]],"date-time":"2023-06-07T23:18:24Z","timestamp":1686179904000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Epigenetic Regulation of Hepatic Lipid Metabolism by DNA Methylation"],"prefix":"10.1002","volume":"10","author":[{"given":"Shirong","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Biology Georgia State University  Atlanta GA 30303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Zha","sequence":"additional","affiliation":[{"name":"Department of Biology Georgia State University  Atlanta GA 30303 USA"},{"name":"The Northern Medical District Chinese PLA General Hospital  Beijing 100094 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Biology Georgia State University  Atlanta GA 30303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010Te","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University of Maryland School of Medicine  Baltimore MD 21201 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruochuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Chemistry and the Center for Diagnosis and Therapeutics Georgia State University  Atlanta GA 30303"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Jing","sequence":"additional","affiliation":[{"name":"Department of Biology Georgia State University  Atlanta GA 30303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huidong","family":"Shi","sequence":"additional","affiliation":[{"name":"GRU Cancer Center and Department of Biochemistry and Molecular Biology Medical College of Georgia Augusta University  Augusta GA 30912 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiping","family":"Chen","sequence":"additional","affiliation":[{"name":"Genomic Core Lab of National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health  Bethesda MD 20855 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Hanover","sequence":"additional","affiliation":[{"name":"Genomic Core Lab of National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health  Bethesda MD 20855 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Chemistry and the Center for Diagnosis and Therapeutics Georgia State University  Atlanta GA 30303"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqing","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University of Maryland School of Medicine  Baltimore MD 21201 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingzhong","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Biology Georgia State University  Atlanta GA 30303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6472-3302","authenticated-orcid":false,"given":"Hang","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Biology Georgia State University  Atlanta GA 30303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,6,6]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1204265"},{"key":"e_1_2_9_2_1","first-page":"1999","volume":"158","author":"Eslam M.","year":"2020","journal-title":"International Consensus Panel"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2009.12.007"},{"key":"e_1_2_9_4_1","first-page":"143","volume":"44","author":"Luczak M. 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