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Endoplasmic Reticulum Stress-Induced Activation of Activating Transcription Factor 6 Decreases cAMP-Stimulated Hepatic Gluconeogenesis via Inhibition of CREB

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Author(s)
Hye-Young SeoMi-Kyung KimAe-Kyung MinHye-Soon KimSeong-Yeol RyuNam-Kyeong KimKyeong Min LeeHan-Jong KimHueng-Sik ChoiKi-Up LeeKeun-Gyu ParkIn-Kyu Lee
Keimyung Author(s)
Kim, Mi KyungKim, Hye SoonRyu, Seong YeolPark, Keun Gyu
Department
Dept. of Internal Medicine (내과학)
Journal Title
Endocrinology
Issued Date
2010
Volume
151
Issue
2
Abstract
The expression of genes encoding key hepatic gluconeogenic enzymes, including phosphoenolpyruvate
carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), is regulated at the transcriptional
level by a network of transcription factors and cofactors, including cAMP response
element-binding protein (CREB). It has been suggested that increased endoplasmic reticulum (ER)
stress in the liver impairs hepatic glucose metabolism. However, the direct effect of ER stress on
hepatic gluconeogenesis is still not clear. Here, we investigated whether ER stress influences hepatic
gluconeogenesis and whether this process is mediated by activating transcription factor 6
(ATF6) through the inhibition of cAMP-mediated activation of CREB. A cAMP stimulant, forskolin,
and 8-bromoadenosine-cAMP increased PEPCK and G6Pase mRNA expression in H4IIE rat hepatoma
cells, and ER stress induced by tunicamycin or thapsigargin decreased the expression of these
genes in forskolin or 8-bromoadenosine-cAMP-treated cells. In a transient transfection study, ATF6
inhibited the PEPCK and G6Pase promoters. Also, adenovirus-mediated overexpression of ATF6 in
H4IIE cells decreased forskolin-stimulated PEPCK and G6Pase gene expression. Moreover, the inhibition
of endogenous ATF6 expression by small interfering RNAs restored the ER stress-induced
suppression of PEPCK and G6Pase gene expression. Transient transfection of ATF6 inhibited transactivation
by CREB on the PEPCK and G6Pase promoters, and a gel shift assay showed that Ad-ATF6
inhibits forskolin-stimulated CREB DNA-binding activity. Finally, we found that expression of ATF6
decreased fasting-induced PEPCK, G6Pase mRNA expression, and blood glucose levels in mice.
Taken together, these data extend our understanding of ER stress and the regulation of liver
gluconeogenesis by ATF6. (Endocrinology 151: 561–568, 2010)
Keimyung Author(s)(Kor)
김미경
김혜순
류성열
박근규
Publisher
School of Medicine
Citation
Hye-Young Seo et al. (2010). Endoplasmic Reticulum Stress-Induced Activation
of Activating Transcription Factor 6 Decreases
cAMP-Stimulated Hepatic Gluconeogenesis via
Inhibition of CREB. Endocrinology, 151(2), 561–568. doi: 10.1210/en.2009-0641#sthash.vQIrFukx.dpuf
Type
Article
ISSN
0013-7227
DOI
10.1210/en.2009-0641#sthash.vQIrFukx.dpuf
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/35623
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Internal Medicine (내과학)
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