title: Impaired oxidative endoplasmic reticulum stress response caused by deficiency of thyroid hormone receptor α.
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.
authors.affiliation: From the Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo-shi, Yamanashi 409-3898, Japan and.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Takahashi
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Furuya
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shimura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kaneshige
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D007340:Insulinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D037021:Thyroid Hormone Receptors alpha / Q000172:deficiency* / Q000235:genetics
chemical_list: C081452:Atf4 protein, mouse; D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D037021:Thyroid Hormone Receptors alpha; D051701:Activating Transcription Factor 4; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine
keywords: Diabetes; Endoplasmic Reticulum Stress; Islet; Thyroid; Thyroid Hormone