Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Proteasomal degradation of retinoid X receptor α reprograms transcriptional activity of PPARγ in obese mice and humans
Bruno Lefebvre, … , Bart Staels, Philippe Lefebvre
Bruno Lefebvre, … , Bart Staels, Philippe Lefebvre
Published April 1, 2010
Citation Information: J Clin Invest. 2010;120(5):1454-1468. https://doi.org/10.1172/JCI38606.
View: Text | PDF
Research Article Endocrinology

Proteasomal degradation of retinoid X receptor α reprograms transcriptional activity of PPARγ in obese mice and humans

  • Text
  • PDF
Abstract

Obese patients have chronic, low-grade inflammation that predisposes to type 2 diabetes and results, in part, from dysregulated visceral white adipose tissue (WAT) functions. The specific signaling pathways underlying WAT dysregulation, however, remain unclear. Here we report that the PPARγ signaling pathway operates differently in the visceral WAT of lean and obese mice. PPARγ in visceral, but not subcutaneous, WAT from obese mice displayed increased sensitivity to activation by its agonist rosiglitazone. This increased sensitivity correlated with increased expression of the gene encoding the ubiquitin hydrolase/ligase ubiquitin carboxyterminal esterase L1 (UCH-L1) and with increased degradation of the PPARγ heterodimerization partner retinoid X receptor α (RXRα), but not RXRβ, in visceral WAT from obese humans and mice. Interestingly, increased UCH-L1 expression and RXRα proteasomal degradation was induced in vitro by conditions mimicking hypoxia, a condition that occurs in obese visceral WAT. Finally, PPARγ-RXRβ heterodimers, but not PPARγ-RXRα complexes, were able to efficiently dismiss the transcriptional corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT) upon agonist binding. Increasing the RXRα/RXRβ ratio resulted in increased PPARγ responsiveness following agonist stimulation. Thus, the selective proteasomal degradation of RXRα initiated by UCH-L1 upregulation modulates the relative affinity of PPARγ heterodimers for SMRT and their responsiveness to PPARγ agonists, ultimately activating the PPARγ-controlled gene network in visceral WAT of obese animals and humans.

Authors

Bruno Lefebvre, Yacir Benomar, Aurore Guédin, Audrey Langlois, Nathalie Hennuyer, Julie Dumont, Emmanuel Bouchaert, Catherine Dacquet, Luc Pénicaud, Louis Casteilla, Francois Pattou, Alain Ktorza, Bart Staels, Philippe Lefebvre

×

Figure 6

Ligand-dependent dismissal of SMRT from PPARγ depends on its association with RXR isotypes.

Options: View larger image (or click on image) Download as PowerPoint
Ligand-dependent dismissal of SMRT from PPARγ depends on its association...
(A) Cofactor interaction in yeast. Vectors encoding for the VP16-AD alone (AD only), or in frame with the NRID of Med1 (VP16-Med1), SMRT (VP16-SMRT), or NCoR (VP16-NCoR), were coexpressed with the PPARγ LBD fused to the Gal4 DBD. Fluorescence is expressed as arbitrary units. (B) Cofactor interaction in mammalian cells. An experimental strategy similar to that described in A was used to monitor Med1, SMRT, or NCoR interaction with the PPARγ LBD in HeLa cells. The basal level observed in the presence of VP16-AD and Gal4-PPARγ LBD was arbitrarily set to 1. (C) SMRT interaction with PPARγ LBD in a cell-free system. A GST-SMRT fusion protein was incubated with radiolabeled PPAR1 and PPAR2, with increasing concentrations of RSG. GST-SMRT–PPARγ complexes were resolved by SDS-PAGE and autoradiographed. (D) Corepressor interaction with aP2 or Adpn promoters in adipocytes. ChIP assays were carried out in differentiated 3T3-L1 cells to detect SMRT or NCoR loading to the aP2 or Adpn promoters. All experiments were carried out at least 3 times. (E) Promoter occupancy by deacetylases. ChIP assays were carried out as in D to detect either SIRT1 or HDAC3 binding to the aP2 or Adpn PPREs. Numbers below blots indicate level of binding relative to DMSO control, arbitrarily set to 1.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts