All‐trans‐retinoic acid ameliorates hepatic steatosis by activating Hes6, a novel transcriptional repressor in mice (901.2)

Abstract

Mice deficient orphan nuclear receptor Small Heterodimer Partner (SHP) are protected from diet‐induced hepatic steatosis due to increased fatty acid oxidation and decreased lipogenesis. Especially the mice exhibited very low expression of peroxisome proliferator activated receptor gamma 2 (Pparγ2), a potent adipogenic transcription factor, in the liver after long‐term western diet (WestD) regimen. We have identified a hairy and enhancer split 6 (Hes6), a novel transcriptional repressor, as an important mediator for the regulation of Pparγ2 expression by SHP using Illumina Beadchip array and realtime PCR analysis in the RNAs isolated from livers of SHP‐/‐ and SHP‐overexpressing mice. The repression of Pparγ2 expression by Hes6 is achieved via its direct repression of hepatocyte nuclear factor 4 alpha (Hnf4α) transcriptional activity. The Hes6 promoter is specifically activated by the retinoic acid receptor (RAR) in response to its natural agonist all‐trans retinoic acid (atRA), and is repressed by SHP. Treatment of atRA or adenovirus‐mediated RARα overexpression in obese mice increased Hes6 mRNA levels and significantly reduced hepatic fat accumulation along with the decreased expression of Pparγ2 and its downstream target gene, fat specific protein 27 (Fsp27). Furthermore, adenovirus‐mediated Hes6 overexpression significantly reduced triglyceride concentration and the expression of Pparγ2 and Fsp27 in the livers of WestD‐fed mice. The current study identifies a novel transcriptional regulatory cascade controlling lipid metabolism and provides insights into new therapeutic approaches to fatty liver diseases.Grant Funding Source: This study is supported by NIH grant R01DK093774.