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

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 (...

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Published in:Endocrinology (Philadelphia) 2010-02, Vol.151 (2), p.561-568
Main Authors: Seo, Hye-Young, Kim, Mi-Kyung, Min, Ae-Kyung, Kim, Hye-Soon, Ryu, Seong-Yeol, Kim, Nam-Kyeong, Lee, Kyeong Min, Kim, Han-Jong, Choi, Hueng-Sik, Lee, Ki-Up, Park, Keun-Gyu, Lee, In-Kyu
Format: Article
Language:English
Subjects:
8-Bromo Cyclic Adenosine Monophosphate - pharmacology
Activating Transcription Factor 6 - genetics
Activating Transcription Factor 6 - physiology
Animals
Biological and medical sciences
Carcinoma, Hepatocellular
Cell Line, Tumor
Colforsin - pharmacology
CREB-Binding Protein - antagonists & inhibitors
CREB-Binding Protein - genetics
Cyclic AMP - pharmacology
Endoplasmic Reticulum - physiology
Fundamental and applied biological sciences. Psychology
Gluconeogenesis - drug effects
Hep G2 Cells - drug effects
Hep G2 Cells - physiology
Humans
Liver - drug effects
Liver - physiology
Liver Neoplasms
Mice
Rats
RNA Splicing
RNA, Messenger - genetics
RNA, Small Interfering - genetics
Thapsigargin - pharmacology
Tunicamycin - pharmacology
Vertebrates: endocrinology
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Summary: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. Endoplasmic reticulum stress-induced activation of activating transcription factor 6 ATF6 decreases fasting-induced hepatic gluconeogenesis via inhibition of cAMP-stimulated CREB activation.
ISSN:0013-7227
1945-7170
DOI:10.1210/en.2009-0641