期刊
METABOLISM-CLINICAL AND EXPERIMENTAL
卷 61, 期 8, 页码 1118-1128出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1016/j.metabol.2012.01.004
关键词
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资金
- Ministry of Health, Labor and Welfare of Japan [H16-genome-003]
- Ministry of Education, Science, Sports and Culture of Japan
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [21591147, 22126006, 24659174, 23390238, 24659439] Funding Source: KAKEN
Activating transcription factor 6 alpha (ATF6 alpha) is essential for the endoplasmic reticulum (ER) stress response. Since recent studies suggested that ER stress is involved in the pathogenesis of type 2 diabetes mellitus, we have analyzed Atf6 alpha-null (Atf6 alpha(-/-)) mice challenged with metabolic overload or genetic manipulations. Atf6 alpha(-/-) mice were fed a high-fat diet to create diet-induced obese (DO) mice, and were subjected to examination of glucose homeostasis with biochemical and morphological analysis of the pancreatic beta-cell and liver tissues. Atf6 alpha-null mice were also crossed with genetic models of diabetes caused either by insulin resistance (Agouti obese mice) or by impaired insulin secretion (Ins2(WT/C96Y) mice). Atf6 alpha(-/-) DO mice were less glucose tolerant with blunted insulin secretion compared to littermates on a high-fat diet. Pancreatic insulin content was lower in Atf6 alpha(-/-) DO mice with the swollen beta-cell ER, a typical feature of cells with ER stress. In the liver of Atf6 alpha(-/-) DO mice, XBP-1 splicing was increased, suggesting that higher ER stress was present. ATF6-deficient mice showed increased mRNA expressions of glucose-6-phosphatase and SREBP1c associated with a tendency for a higher degree of steatosis in the liver. However, Atf6 alpha(-/-) DO mice exhibited higher insulin sensitivity with lower serum triglyceride levels. Similar phenotypes were observed in ATF6 alpha-deficient Agouti mice. In addition, ATF6 alpha-deficiency accelerated reduction in pancreatic insulin content in Ins2(WT/C96Y) mice. These data suggested that ATF6 alpha contributes to both prevention and promotion of diabetes; it protects beta-cells from ER stress and suppresses hepatosteatosis, but plays a role in the development of hyperlipidemia and insulin resistance. (C) 2012 Elsevier Inc. All rights reserved.
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