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Peroxisome proliferator‐activated receptor gamma (PPARγ) is a master regulator for white adipocyte differentiation and lipid storage. The increased level of hepatic PPARγ2 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  Pparg2  expression and hepatic steatosis induced by diet. Liver‐specific overexpression of  Hes6  using adenovirus reduced  Pparg2  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  Hes6  gene expression using short hairpin RNA increased hepatic lipid accumulation and  Pparg2  messenger RNA levels by 70% and 4‐fold, respectively. To locate hepatocyte nuclear factor 4 alpha (HNF4α) binding site(s), through which repressional activity of HES6 is mediated, a 2.5‐kb  Pparg2  promoter‐driven luciferase reporter was constructed for transient transfection assays. Subsequently, chromatin immunoprecipitation and electrophoretic mobility shift assays were performed. An HNF4α binding consensus sequence was identified at 903 base pairs upstream from the transcription start site of  Pparg2 . Deletion or point mutation of the sequence in a luciferase reporter containing the  Pparg2  promoter abolished HNF4α‐mediated activation in HeLa cells. Chromatin immunoprecipitation and electrophoretic mobility shift assays further confirmed direct recruitment and binding of HNF4α to the site. Gene expression analysis with liver samples from subjects with nonalcoholic steatohepatitis suggested that the axis of the Hes6–Hnf4a–Pparg2 transcriptional cascade is also responsible for hepatic fat accumulation in humans.  Conclusion : HES6 represses  Pparg2  gene expression, thereby preventing hepatic lipid accumulation induced by chronic Western diet feeding or pathophysiologic conditions. ( Hepatology Communications  2017;1:1085–1098)

Hairy and enhancer of split 6 prevents hepatic lipid accumulation through inhibition of Pparg2 expression