| First Author | Takahashi K | Year | 2014 |
| Journal | J Biol Chem | Volume | 289 |
| Issue | 18 | Pages | 12485-93 |
| PubMed ID | 24644288 | Mgi Jnum | J:213174 |
| Mgi Id | MGI:5583001 | Doi | 10.1074/jbc.M113.544122 |
| Citation | Takahashi K, et al. (2014) Impaired oxidative endoplasmic reticulum stress response caused by deficiency of thyroid hormone receptor alpha. J Biol Chem 289(18):12485-93 |
| abstractText | Thyroid hormone receptor alpha (TRalpha) is critical to postnatal pancreatic beta-cell maintenance. To investigate the association between TRalpha and the survival of pancreatic beta-cells under endoplasmic reticulum (ER) stress, the expression of endogenous TRalpha was inhibited by infection with an adenovirus expressing double-stranded short hairpin RNA against TRalpha (AdshTRalpha). In control adenovirus-infected pancreatic beta-cells, palmitate enhanced the expression of activating transcription factor 4 (ATF4) and heme oxygenase 1, which facilitates adaptation to oxidative ER stress. However, in AdshTRalpha-infected pancreatic beta-cells, palmitate did not induce ATF4-mediated integrated stress response, and oxidative stress-associated apoptotic cell death was significantly enhanced. TRalpha-deficient mice or wild-type mice (WT) were fed a high fat diet (HFD) for 30 weeks, and the effect of oxidative ER stress on pancreatic beta-cells was analyzed. HFD-treated TRalpha-deficient mice had high blood glucose levels and low plasma insulin levels. In HFD-treated TRalpha-deficient mice, ATF4 was not induced, and apoptosis was enhanced compared with HFD-treated WT mice. Furthermore, the expression level of 8-hydroxydeoxyguanosine, an oxidative stress marker, was enhanced in the beta-cells of HFD-treated TRalpha-deficient mice. These results indicate that endogenous TRalpha plays an important role for the expression of ATF4 and facilitates reduced apoptosis in pancreatic beta-cells under ER stress. |
