Rexinoids Modulate Steroid and Xenobiotic Receptor Activity by Increasing Its Protein Turnover in a Calpain-dependent Manner

Pettersson, Filippa; Hanna, Nessrine; Lagodich, Marina; Dupéré-Richér, Daphne; Couture, Marie-Claude; Choi, Catherine H.; Miller, Wilson H.

doi:10.1074/jbc.m710358200

Cited by 10 publications

(13 citation statements)

References 40 publications

(47 reference statements)

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“…In agreement with these observations, CoCl 2 , an agent mimicking partially hypoxia through HIF1α induction and stabilization, was found to increase UCH-L1 expression in 3T3-L1 adipocytes and to promote RXRα protein breakdown in a UCH-L1-dependent manner. RXRα is a known target of the UPS in several cell types (31)(32)(33)(34)(35), and our present data showed that RXRα was a substrate for in vitro ubiquitin conjugation, whereas RXRβ was unable to undergo this posttranslational modification. However, recombinant UCH-L1 neither modified the ubiquitin conjugation rate in the acellular system nor engaged direct protein-protein interaction with RXRα in vitro, as assayed by GST-pulldown assays (data not shown), which suggests that this enzyme promotes RXRα breakdown in an indirect manner.…”

Section: Discussionmentioning

confidence: 69%

“…Rxr mRNA levels were similar in WAT of OB/OB and ob/ob mice fed a regular diet (LFD) or high-fat diet (HFD). However, RXRα activity has previously been shown to be regulated by protein degradation in several cell types (31)(32)(33)(34)(35). We thus investigated whether RXRα polypeptide stability is affected in visWAT and scWAT of OB/OB and ob/ob mice.…”

Section: Resultsmentioning

confidence: 99%

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

Lefebvre

Benomar²,

Guédin³

et al. 2010

J. Clin. Invest.

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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. IntroductionFrom a clinical perspective, visceral obesity predisposes to an increased incidence of type 2 diabetes mellitus (T2DM) and associated cardiovascular diseases (1, 2). The visceral white adipose tissue (visWAT; i.e., epididymal WAT) depot is believed to contribute to the low-grade, chronic inflammatory state that occurs in obese patients and animals and favors the progression toward T2DM. This feature stems from the specific functional properties of adipocytes from this WAT depot, which are highly sensitive to β-adrenergic stimulation and relatively resistant to the antilipolytic effects of insulin compared with subcutaneous adipocytes (3). Indeed, although subcutaneous WAT (scWAT; i.e., inguinal WAT) is predominantly, but not exclusively, a lipid storage tissue exhibiting a high adipocyte plasticity, visWAT also triggers complex endocrine regulations by releasing FFAs, hormones, and cytokines that reach the liver through the portal vein (reviewed in ref. 4). How visWAT functions are affected upon disease progression is unknown, but metabolic challenges increase the release of proinflammatory cytokines and decrease that of insulin-sensitizing adipokines by visWAT.Results from recent clinical trials (ADOPT, DREAM, and PRO-ACTIVE; ref. 5) indicate that the insulin-sensitizing thiazolidin-

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Section: Discussionmentioning

confidence: 69%

Section: Resultsmentioning

confidence: 99%

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

Lefebvre

Benomar²,

Guédin³

et al. 2010

J. Clin. Invest.

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show abstract

“…In contrast, a number of reports documented the proteasomal degradation of RXRα in various cellular backgrounds 37 , which appeared to be conditioned by RXR interaction with RAR and the corepressor SMRT 38,39 and increased upon agonist binding 40,41 . Moreover, RXRα breakdown is dependent on MAPK or PKC activity 42,43 , hinting at a link between RXRα phosphorylation and proteasomal-mediated degradation 44 .…”

Section: 5mentioning

confidence: 95%

Retinoid X receptors: common heterodimerization partners with distinct functions

Lefèbvre

Benomar²,

Staels

2010

Trends in Endocrinology & Metabolism

264

224

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“…Many nuclear receptors are regulated by modulation of protein expression. 29,30 Therefore, we also investigated whether As 2 O 3 decreased LXR␣/ LXR␤ protein expression. Immunoblotting experiments, using extracts from RAW 264.7 and THP-1 cells treated with 22R-OHC/9-cis-RA in the absence or presence of 1 to 5 mol/L of As 2 O 3 , showed no significant alteration of LXR␣/LXR␤ protein levels (Supplemental Figure IIB).…”

Section: As 2 O 3 Does Not Alter Nuclear Receptor Expression or Hetermentioning

confidence: 99%

Inhibition of Liver X Receptor/Retinoid X Receptor–Mediated Transcription Contributes to the Proatherogenic Effects of Arsenic in Macrophages In Vitro

Padovani

Molina

Mann

2010

ATVB

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Objective-To determine whether arsenic inhibits transcriptional activation of the liver X receptor (LXR)/retinoid X receptor (RXR) heterodimers, thereby impairing cholesterol efflux from macrophages and potentially contributing to a proatherogenic phenotype. Methods and Results-Arsenic is an important environmental contaminant and has been linked to an increased incidence of atherosclerosis. Previous findings showed that arsenic inhibits transcriptional activation of type 2 nuclear receptors, known to heterodimerize with RXR. Environmentally relevant arsenic doses decrease the LXR/RXR ligand-induced expression of the LXR target genes . Arsenic failed to decrease cAMP-induced ABCA1 expression, suggesting a selective LXR/RXR effect. This selectivity correlated with the ability of arsenic to decrease LXR/RXR ligand-induced, but not cAMP-induced, cholesterol efflux. By using chromatin immunoprecipitation assays, we found that arsenic inhibits the ability of LXR/RXR ligands to induce activation markers on the ABCA1 and SREBP-1c promoters and blocks ligand-induced release of the nuclear receptor coexpressor (NCoR) from the promoter. Arsenic did not alter the ability of LXR to transrepress inflammatory gene transcription, further supporting our hypothesis that RXR is the target for arsenic inhibition. Conclusion-Exposure to arsenic enhances the risk of atherosclerosis. We present data that arsenic inhibits the transcriptional activity of the liver X receptor, resulting in decreased cholesterol-induced gene expression and efflux from macrophages. Therefore, arsenic may promote an athersclerotic environment by decreasing the ability of macrophages to efflux excess cholesterol, thereby favoring increased plaque formation. Key Words: atherosclerosis Ⅲ macrophages Ⅲ receptors Ⅲ arsenic Ⅲ liver X receptor A rsenic has been widely known as a carcinogen; however, recent evidence suggests that those exposed to arsenic also have an increased risk for diabetes mellitus and cardiovascular diseases. In humans, a consequence of arsenic exposure is Blackfoot disease, which is characterized by severe peripheral arteriosclerosis. [1][2][3] Copper smelt workers exposed to arsenic were reported to have increased mortality from ischemic heart disease. 4,5 A significant correlation was found in an area of Taiwan between length of exposure to arsenic in the ground water and the risk of ischemic heart disease. 6 In the United States, higher levels in the drinking water correlated with an increased risk of death from vascular disease. 7 More recently, arsenic accelerated carotid atherosclerosis, with a multivariate-adjusted odds ratio of 3.1. 8 In vivo and in vitro data support and correlate with these epidemiological data, although the mechanism by which arsenic increases atherosclerosis is unclear. Inflammation is a key component of the generation of atherosclerotic lesions, and increased inflammatory molecule expression after arsenic exposure has been reported. 9 Cells treated in vitro with arsenic have increased levels of 5-lipoxygenase, ...

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Rexinoids Modulate Steroid and Xenobiotic Receptor Activity by Increasing Its Protein Turnover in a Calpain-dependent Manner

Cited by 10 publications

References 40 publications

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

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

Retinoid X receptors: common heterodimerization partners with distinct functions

Inhibition of Liver X Receptor/Retinoid X Receptor–Mediated Transcription Contributes to the Proatherogenic Effects of Arsenic in Macrophages In Vitro

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