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Retinoid X receptor α overexpression alleviates mitochondrial dysfunction-induced insulin resistance through transcriptional regulation of insulin receptor substrate 1.

Lee SE, Koo YD, Lee JS, Kwak SH, Jung HS, Cho YM, Park YJ, Chung SS, Park KS - Mol. Cells (2015)

Bottom Line: RXRα overexpression also increased IRS1 transcription and mitochondrial function.Because RXRα overexpression, knock-down, or activation by LG1506 regulated IRS1 transcription mostly independently of mitochondrial function, it is likely that RXRα directly regulates IRS1 transcription.Consistent with the hypothesis, we showed that RXRα bound to the IRS1 promoter as a heterodimer with peroxisome proliferator-activated receptor δ (PPARδ).

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.

ABSTRACT
Mitochondrial dysfunction is associated with insulin resistance and diabetes. We previously showed that retinoid X receptor α (RXRα) played an important role in transcriptional regulation of oxidative phosphorylation (OXPHOS) genes in cells with mitochondrial dysfunction caused by mitochondrial DNA mutation. In this study, we investigated whether mitochondrial dysfunction induced by incubation with OXPHOS inhibitors affects insulin receptor substrate 1 (IRS1) mRNA and protein levels and whether RXRα activation or overexpression can restore IRS1 expression. Both IRS1 and RXRα protein levels were significantly reduced when C2C12 myotubes were treated with the OXPHOS complex inhibitors, rotenone and antimycin A. The addition of RXRα agonists, 9-cis retinoic acid (9cRA) and LG1506, increased IRS1 transcription and protein levels and restored mitochondrial function, which ultimately improved insulin signaling. RXRα overexpression also increased IRS1 transcription and mitochondrial function. Because RXRα overexpression, knock-down, or activation by LG1506 regulated IRS1 transcription mostly independently of mitochondrial function, it is likely that RXRα directly regulates IRS1 transcription. Consistent with the hypothesis, we showed that RXRα bound to the IRS1 promoter as a heterodimer with peroxisome proliferator-activated receptor δ (PPARδ). These results suggest that RXRα overexpression or activation alleviates insulin resistance by increasing IRS1 expression.

No MeSH data available.


Related in: MedlinePlus

RXRα overexpression prevents rotenone-induced suppression of IRS1 transcription. C2C12 myotubes were infected with Ad-RXRα (50 MOI) for 48 h and then treated with rotenone for an additional 24 h. (A) Western blot analysis and (B) real-time PCR were performed (n = 6). P < 0.05 vs. Ad-GFP; #, P < 0.05 vs. Ad-GFP with rotenone. (C) Insulin was treated for 15 min before harvesting and western blot analysis was performed. (D) Cellular ATP contents were measured (n = 7). *, P < 0.05 vs. Ad-GFP; #, P < 0.05 vs. Ad-GFP with rotenone.
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f2-molce-38-4-356: RXRα overexpression prevents rotenone-induced suppression of IRS1 transcription. C2C12 myotubes were infected with Ad-RXRα (50 MOI) for 48 h and then treated with rotenone for an additional 24 h. (A) Western blot analysis and (B) real-time PCR were performed (n = 6). P < 0.05 vs. Ad-GFP; #, P < 0.05 vs. Ad-GFP with rotenone. (C) Insulin was treated for 15 min before harvesting and western blot analysis was performed. (D) Cellular ATP contents were measured (n = 7). *, P < 0.05 vs. Ad-GFP; #, P < 0.05 vs. Ad-GFP with rotenone.

Mentions: Next, we tested whether RXRα protein level itself affects rote-none-suppressed IRS1 mRNA or protein levels. When RXRα was overexpressed using an adenoviral system, IRS1 protein levels were also increased in the presence of rotenone (Fig. 2A). Consistent with this finding, IRS1 mRNA levels were also increased following RXRα overexpression (Fig. 2B). In addition, RXRα overexpression prevented rotenone-induced insulin signaling impairment (Fig. 2C). We also assessed the effect of RXRα overexpression on mitochondrial function. ATP contents were significantly recovered by RXRα overexpression in the presence of rotenone (Fig. 2D). These results suggest that RXRα overexpression was sufficient to reverse decreased IRS transcription and mitochondrial dysfunction induced by rote-none.


Retinoid X receptor α overexpression alleviates mitochondrial dysfunction-induced insulin resistance through transcriptional regulation of insulin receptor substrate 1.

Lee SE, Koo YD, Lee JS, Kwak SH, Jung HS, Cho YM, Park YJ, Chung SS, Park KS - Mol. Cells (2015)

RXRα overexpression prevents rotenone-induced suppression of IRS1 transcription. C2C12 myotubes were infected with Ad-RXRα (50 MOI) for 48 h and then treated with rotenone for an additional 24 h. (A) Western blot analysis and (B) real-time PCR were performed (n = 6). P < 0.05 vs. Ad-GFP; #, P < 0.05 vs. Ad-GFP with rotenone. (C) Insulin was treated for 15 min before harvesting and western blot analysis was performed. (D) Cellular ATP contents were measured (n = 7). *, P < 0.05 vs. Ad-GFP; #, P < 0.05 vs. Ad-GFP with rotenone.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4400311&req=5

f2-molce-38-4-356: RXRα overexpression prevents rotenone-induced suppression of IRS1 transcription. C2C12 myotubes were infected with Ad-RXRα (50 MOI) for 48 h and then treated with rotenone for an additional 24 h. (A) Western blot analysis and (B) real-time PCR were performed (n = 6). P < 0.05 vs. Ad-GFP; #, P < 0.05 vs. Ad-GFP with rotenone. (C) Insulin was treated for 15 min before harvesting and western blot analysis was performed. (D) Cellular ATP contents were measured (n = 7). *, P < 0.05 vs. Ad-GFP; #, P < 0.05 vs. Ad-GFP with rotenone.
Mentions: Next, we tested whether RXRα protein level itself affects rote-none-suppressed IRS1 mRNA or protein levels. When RXRα was overexpressed using an adenoviral system, IRS1 protein levels were also increased in the presence of rotenone (Fig. 2A). Consistent with this finding, IRS1 mRNA levels were also increased following RXRα overexpression (Fig. 2B). In addition, RXRα overexpression prevented rotenone-induced insulin signaling impairment (Fig. 2C). We also assessed the effect of RXRα overexpression on mitochondrial function. ATP contents were significantly recovered by RXRα overexpression in the presence of rotenone (Fig. 2D). These results suggest that RXRα overexpression was sufficient to reverse decreased IRS transcription and mitochondrial dysfunction induced by rote-none.

Bottom Line: RXRα overexpression also increased IRS1 transcription and mitochondrial function.Because RXRα overexpression, knock-down, or activation by LG1506 regulated IRS1 transcription mostly independently of mitochondrial function, it is likely that RXRα directly regulates IRS1 transcription.Consistent with the hypothesis, we showed that RXRα bound to the IRS1 promoter as a heterodimer with peroxisome proliferator-activated receptor δ (PPARδ).

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.

ABSTRACT
Mitochondrial dysfunction is associated with insulin resistance and diabetes. We previously showed that retinoid X receptor α (RXRα) played an important role in transcriptional regulation of oxidative phosphorylation (OXPHOS) genes in cells with mitochondrial dysfunction caused by mitochondrial DNA mutation. In this study, we investigated whether mitochondrial dysfunction induced by incubation with OXPHOS inhibitors affects insulin receptor substrate 1 (IRS1) mRNA and protein levels and whether RXRα activation or overexpression can restore IRS1 expression. Both IRS1 and RXRα protein levels were significantly reduced when C2C12 myotubes were treated with the OXPHOS complex inhibitors, rotenone and antimycin A. The addition of RXRα agonists, 9-cis retinoic acid (9cRA) and LG1506, increased IRS1 transcription and protein levels and restored mitochondrial function, which ultimately improved insulin signaling. RXRα overexpression also increased IRS1 transcription and mitochondrial function. Because RXRα overexpression, knock-down, or activation by LG1506 regulated IRS1 transcription mostly independently of mitochondrial function, it is likely that RXRα directly regulates IRS1 transcription. Consistent with the hypothesis, we showed that RXRα bound to the IRS1 promoter as a heterodimer with peroxisome proliferator-activated receptor δ (PPARδ). These results suggest that RXRα overexpression or activation alleviates insulin resistance by increasing IRS1 expression.

No MeSH data available.


Related in: MedlinePlus