Aldose Reductase Acts as a Selective Derepressor of PPARγ and the Retinoic Acid Receptor

• DOI: 10.1016/j.celrep.2016.02.086
• Publication Date: 2016-03-24T16:02:24Z
• Authors: Devi Thiagarajan; Radha Ananthakris...; Jinghua Zhang; Karen M. O’Shea; Nosirudeen Quadri; Qing Li; Kelli Sas; Xiao Jing; Rosa Rosario; Subramaniam Penna...; Ann Marie Schmidt; Ravichandran Rama...
• Keywords: Corepressor; HDAC3; Histone deacetylase 2; Retinoid X receptor

Histone deacetylase 3 (HDAC3), a chromatin-modifying enzyme, requires association with the deacetylase-containing domain (DAD) of nuclear receptor corepressors NCOR1 and SMRT for its stability activity. Here, we show that aldose reductase (AR), rate-limiting enzyme polyol pathway, competes HDAC3 to bind NCOR1/SMRT DAD. Increased AR expression leads degradation followed by increased PPARγ signaling, resulting in lipid accumulation heart. also downregulates corepressor complex cofactors including Gps2 Tblr1, thus affecting activity itself. Though reduces HDAC3-corepressor formation, it specifically derepresses retinoic acid (RAR), but not other receptors such as thyroid (TR) liver X (LXR). In summary, this work defines distinct role retinoid metabolism through regulation consequent derepression RAR.