{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T16:51:21Z","timestamp":1788886281987,"version":"build-2803163510"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","license":[{"start":{"date-parts":[[2017,11,8]],"date-time":"2017-11-08T00:00:00Z","timestamp":1510099200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatology Communications"],"published-print":{"date-parts":[[2017,12]]},"abstract":"<jats:p>Peroxisome proliferator\u2010activated receptor gamma (PPAR\u03b3) is a master regulator for white adipocyte differentiation and lipid storage. The increased level of hepatic PPAR\u03b32 isoform reprograms liver for lipid storage and causes abnormal fat accumulation in certain pathophysiologic conditions. The current study aimed to investigate a role of transcriptional repressor hairy and enhancer of split 6 (HES6) in the regulation of <jats:italic toggle=\"yes\">Pparg2<\/jats:italic> expression and hepatic steatosis induced by diet. Liver\u2010specific overexpression of <jats:italic toggle=\"yes\">Hes6<\/jats:italic> using adenovirus reduced <jats:italic toggle=\"yes\">Pparg2<\/jats:italic> messenger RNA levels by 90% and hepatic triglyceride accumulation by 22% compared to the levels in mice injected with an adenoviral empty vector with Western diet feeding. In sharp contrast, silencing <jats:italic toggle=\"yes\">Hes6<\/jats:italic> gene expression using short hairpin RNA increased hepatic lipid accumulation and <jats:italic toggle=\"yes\">Pparg2<\/jats:italic> messenger RNA levels by 70% and 4\u2010fold, respectively. To locate hepatocyte nuclear factor 4 alpha (HNF4\u03b1) binding site(s), through which repressional activity of HES6 is mediated, a 2.5\u2010kb <jats:italic toggle=\"yes\">Pparg2<\/jats:italic> promoter\u2010driven luciferase reporter was constructed for transient transfection assays. Subsequently, chromatin immunoprecipitation and electrophoretic mobility shift assays were performed. An HNF4\u03b1 binding consensus sequence was identified at 903 base pairs upstream from the transcription start site of <jats:italic toggle=\"yes\">Pparg2<\/jats:italic>. Deletion or point mutation of the sequence in a luciferase reporter containing the <jats:italic toggle=\"yes\">Pparg2<\/jats:italic> promoter abolished HNF4\u03b1\u2010mediated activation in HeLa cells. Chromatin immunoprecipitation and electrophoretic mobility shift assays further confirmed direct recruitment and binding of HNF4\u03b1 to the site. Gene expression analysis with liver samples from subjects with nonalcoholic steatohepatitis suggested that the axis of the Hes6\u2013Hnf4a\u2013Pparg2 transcriptional cascade is also responsible for hepatic fat accumulation in humans. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: HES6 represses <jats:italic toggle=\"yes\">Pparg2<\/jats:italic> gene expression, thereby preventing hepatic lipid accumulation induced by chronic Western diet feeding or pathophysiologic conditions. (<jats:italic toggle=\"yes\">Hepatology Communications<\/jats:italic> 2017;1:1085\u20131098)<\/jats:p>","DOI":"10.1002\/hep4.1120","type":"journal-article","created":{"date-parts":[[2017,11,8]],"date-time":"2017-11-08T09:26:43Z","timestamp":1510133203000},"page":"1085-1098","source":"Crossref","is-referenced-by-count":8,"title":["Hairy and enhancer of split 6 prevents hepatic lipid accumulation through inhibition of Pparg2 expression"],"prefix":"10.1097","volume":"1","author":[{"given":"Jung Eun","family":"Park","sequence":"first","affiliation":[{"name":"Department of Integrative Medical Sciences,Northeast Ohio Medical University,Rootstown,Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikang","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Integrative Medical Sciences,Northeast Ohio Medical 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