详细记录  
题名:Impaired oxidative endoplasmic reticulum stress response caused by deficiency of thyroid hormone receptor alpha
作者:TAKAHASHI K; FURUYA F; SHIMURA H; KANESHIGE M; KOBAYASHI T;
来源:J Biol Chem. 2014 Mar 18. [ IF= 0.00 ] ]
URL :10.1074/jbc.M113.544122
日期:20140408
摘要: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 as compared to 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.

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