title: Aldose Reductase Acts as a Selective Derepressor of PPARγ and the Retinoic Acid Receptor.
abstract: Histone deacetylase 3 (HDAC3), a chromatin-modifying enzyme, requires association with the deacetylase-containing domain (DAD) of the nuclear receptor corepressors NCOR1 and SMRT for its stability and activity. Here, we show that aldose reductase (AR), the rate-limiting enzyme of the polyol pathway, competes with HDAC3 to bind the NCOR1/SMRT DAD. Increased AR expression leads to HDAC3 degradation followed by increased PPARγ signaling, resulting in lipid accumulation in the heart. AR also downregulates expression of nuclear corepressor complex cofactors including Gps2 and Tblr1, thus affecting activity of the nuclear corepressor complex itself. Though AR reduces HDAC3-corepressor complex formation, it specifically derepresses the retinoic acid receptor (RAR), but not other nuclear receptors such as the thyroid receptor (TR) and liver X receptor (LXR). In summary, this work defines a distinct role for AR in lipid and retinoid metabolism through HDAC3 regulation and consequent derepression of PPARγ and RAR.
authors.affiliation: Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Devi
authors.initials: D
authors.lastname: Thiagarajan
authors.affiliation: Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Radha
authors.initials: R
authors.lastname: Ananthakrishnan
authors.affiliation: Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: O'Shea
authors.affiliation: Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Nosirudeen
authors.initials: N
authors.lastname: Quadri
authors.affiliation: Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Division of Nephrology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Kelli
authors.initials: K
authors.lastname: Sas
authors.affiliation: Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Jing
authors.affiliation: Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rosario
authors.affiliation: Division of Nephrology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
authors.affiliation: Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Schmidt
authors.affiliation: Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USA. Electronic address: ramasr02@nyumc.org.
authors.forename: Ravichandran
authors.initials: R
authors.lastname: Ramasamy
mesh_terms: D000449:Aldehyde Reductase / Q000378:metabolism*; D000818:Animals; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000378:metabolism*
chemical_list: D056971:Nuclear Receptor Co-Repressor 1; D047495:PPAR gamma; D018168:Receptors, Retinoic Acid; D000449:Aldehyde Reductase; D006655:Histone Deacetylases