Retinoid X receptor α overexpression alleviates mitochondrial dysfunction-induced insulin resistance through transcriptional regulation of insulin receptor substrate 1.
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.
Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.
Seung Eun
SE
Lee
Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.
Young Do
YD
Koo
Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.
Ji Seon
JS
Lee
Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.
Soo Heon
SH
Kwak
Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.
Hye Seung
HS
Jung
Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.
Young Min
YM
Cho
Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.
Young Joo
YJ
Park
Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.
Sung Soo
SS
Chung
Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.
Kyong Soo
KS
Park
D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000096:biosynthesis / Q000235:genetics*; D007333:Insulin Resistance; D051379:Mice; D008931:Mitochondria, Muscle / Q000235:genetics* / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D047490:Retinoid X Receptor alpha
insulin receptor substrate 1; insulin resistance; itochondrial dysfunction; retinoid X receptor α