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

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,...

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Main Authors: Devi Thiagarajan, Radha Ananthakrishnan, Jinghua Zhang, Karen M. O’Shea, Nosirudeen Quadri, Qing Li, Kelli Sas, Xiao Jing, Rosa Rosario, Subramaniam Pennathur, Ann Marie Schmidt, Ravichandran Ramasamy
Format: Article
Language:English
Published: Elsevier 2016-04-01
Series:Cell Reports
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124716302212
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spelling doaj-8bc77572507b48e6bb6d011a73ad36ea2020-11-24T20:58:46ZengElsevierCell Reports2211-12472016-04-0115118119610.1016/j.celrep.2016.02.086Aldose Reductase Acts as a Selective Derepressor of PPARγ and the Retinoic Acid ReceptorDevi Thiagarajan0Radha Ananthakrishnan1Jinghua Zhang2Karen M. O’Shea3Nosirudeen Quadri4Qing Li5Kelli Sas6Xiao Jing7Rosa Rosario8Subramaniam Pennathur9Ann Marie Schmidt10Ravichandran Ramasamy11Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USADiabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USADiabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USADiabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USADiabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USAColumbia University Medical Center, New York, NY 10032, USADivision of Nephrology, University of Michigan Medical School, Ann Arbor, MI 48109, USADiabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USADiabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USADivision of Nephrology, University of Michigan Medical School, Ann Arbor, MI 48109, USADiabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USADiabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USAHistone 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.http://www.sciencedirect.com/science/article/pii/S2211124716302212
collection DOAJ
language English
format Article
sources DOAJ
author Devi Thiagarajan
Radha Ananthakrishnan
Jinghua Zhang
Karen M. O’Shea
Nosirudeen Quadri
Qing Li
Kelli Sas
Xiao Jing
Rosa Rosario
Subramaniam Pennathur
Ann Marie Schmidt
Ravichandran Ramasamy
spellingShingle Devi Thiagarajan
Radha Ananthakrishnan
Jinghua Zhang
Karen M. O’Shea
Nosirudeen Quadri
Qing Li
Kelli Sas
Xiao Jing
Rosa Rosario
Subramaniam Pennathur
Ann Marie Schmidt
Ravichandran Ramasamy
Aldose Reductase Acts as a Selective Derepressor of PPARγ and the Retinoic Acid Receptor
Cell Reports
author_facet Devi Thiagarajan
Radha Ananthakrishnan
Jinghua Zhang
Karen M. O’Shea
Nosirudeen Quadri
Qing Li
Kelli Sas
Xiao Jing
Rosa Rosario
Subramaniam Pennathur
Ann Marie Schmidt
Ravichandran Ramasamy
author_sort Devi Thiagarajan
title Aldose Reductase Acts as a Selective Derepressor of PPARγ and the Retinoic Acid Receptor
title_short Aldose Reductase Acts as a Selective Derepressor of PPARγ and the Retinoic Acid Receptor
title_full Aldose Reductase Acts as a Selective Derepressor of PPARγ and the Retinoic Acid Receptor
title_fullStr Aldose Reductase Acts as a Selective Derepressor of PPARγ and the Retinoic Acid Receptor
title_full_unstemmed Aldose Reductase Acts as a Selective Derepressor of PPARγ and the Retinoic Acid Receptor
title_sort aldose reductase acts as a selective derepressor of pparγ and the retinoic acid receptor
publisher Elsevier
series Cell Reports
issn 2211-1247
publishDate 2016-04-01
description 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.
url http://www.sciencedirect.com/science/article/pii/S2211124716302212
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