Impaired Oxidative Endoplasmic Reticulum Stress Response Caused by Deficiency of Thyroid Hormone Receptor α

Kazuya Takahashi,Fumihiko Furuya,Hiroki Shimura,Masahiro Kaneshige,Tetsuro Kobayashi

doi:10.1074/jbc.m113.544122

Abstract

Thyroid hormone receptor α (TRα) is critical to postnatal pancreatic β-cell maintenance. To investigate the association between TRα and the survival of pancreatic β-cells under endoplasmic reticulum (ER) stress, the expression of endogenous TRα was inhibited by infection with an adenovirus expressing double-stranded short hairpin RNA against TRα (AdshTRα). In control adenovirus-infected pancreatic β-cells, palmitate enhanced the expression of activating transcription factor 4 (ATF4) and heme oxygenase 1, which facilitates adaptation to oxidative ER stress. However, in AdshTRα-infected pancreatic β-cells, palmitate did not induce ATF4-mediated integrated stress response, and oxidative stress-associated apoptotic cell death was significantly enhanced. TRα-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 β-cells was analyzed. HFD-treated TRα-deficient mice had high blood glucose levels and low plasma insulin levels. In HFD-treated TRα-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 β-cells of HFD-treated TRα-deficient mice. These results indicate that endogenous TRα plays an important role for the expression of ATF4 and facilitates reduced apoptosis in pancreatic β-cells under ER stress.

Highlights

Endoplasmic reticulum (ER) stress is involved in ␤-cell failure and apoptotic death
To explore the mechanisms of thyroid hormone receptor (TR)␣-associated antiapoptotic effects, we focused on the eIF2␣-activating transcription factor 4 (ATF4) pathway in pancreatic ␤-cells under ER stress
In MIN6 cells infected with 30 m.o.i. of AdshTR␣, the expression of TR␣ was completely inhibited after 48 h of incubation

Summary

Background

Endoplasmic reticulum (ER) stress is involved in ␤-cell failure and apoptotic death. Results: Upon endogenous TR␣ knockdown, ER stress significantly enhanced apoptosis in pancreatic ␤-cells. The expression level of 8-hydroxydeoxyguanosine, an oxidative stress marker, was enhanced in the ␤-cells of HFD-treated TR␣-deficient mice These results indicate that endogenous TR␣ plays an important role for the expression of ATF4 and facilitates reduced apoptosis in pancreatic ␤-cells under ER stress. To combat the deleterious effects of ER stress, cells have evolved protective strategies, collectively termed the unfolded protein response (UPR) [6] This concerted and complex cellular response is mediated through ER transmembrane receptors: pancreatic ER kinase-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1). We demonstrated that TR␣ was necessary for the ATF4-mediated antistress response for adaptation to the palmitate-induced oxidative stress This finding clearly shows that TR plays important roles for maintenance of ␤-cell mass under excessive intake of saturated fatty acid

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION