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URL Address
<a href="http://doi.org/10.1074/jbc.M112.339887" target="_blank" rel="noreferrer noopener">http://doi.org/10.1074/jbc.M112.339887</a>
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Pages
37098-37108
Issue
44
Volume
287
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Title
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Orphan Nuclear Receptor Small Heterodimer Partner Negatively Regulates Growth Hormone-mediated Induction Of Hepatic Gluconeogenesis Through Inhibition Of Signal Transducer And Activator Of Transcription 5 (stat5) Transactivation
Publisher
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Journal of Biological Chemistry
Date
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2012
2012-10
Subject
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ampk; ataxia-telangiectasia; atm; Biochemistry & Molecular Biology; expression; Glucose; glucose-6-phosphatase gene; involvement; metformin; protein kinase; shp
Creator
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Kim Y D; Li T G; Ahn S W; Kim D K; Lee J M; Hwang S L; Kim Y H; Lee C H; Lee I K; Chiang J Y L; Choi H S
Description
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Growth hormone (GH) is a key metabolic regulator mediating glucose and lipid metabolism. Ataxia telangiectasia mutated (ATM) is a member of the phosphatidylinositol 3-kinase superfamily and regulates cell cycle progression. The orphan nuclear receptor small heterodimer partner (SHP: NR0B2) plays a pivotal role in regulating metabolic processes. Here, we studied the role of ATM on GH-dependent regulation of hepatic gluconeogenesis in the liver. GH induced phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase gene expression in primary hepatocytes. GH treatment and adenovirus-mediated STAT5 overexpression in hepatocytes increased glucose production, which was blocked by a JAK2 inhibitor, AG490, dominant negative STAT5, and STAT5 knockdown. We identified a STAT5 binding site on the PEPCK gene promoter using reporter assays and point mutation analysis. Up-regulation of SHP by metformin-mediated activation of the ATM-AMP-activated protein kinase pathway led to inhibition of GH-mediated induction of hepatic gluconeogenesis, which was abolished by an ATM inhibitor, KU-55933. Immunoprecipitation studies showed that SHP physically interacted with STAT5 and inhibited STAT5 recruitment on the PEPCK gene promoter. GH-induced hepatic gluconeogenesis was decreased by either metformin or Ad-SHP, whereas the inhibition by metformin was abolished by SHP knockdown. Finally, the increase of hepatic gluconeogenesis following GH treatment was significantly higher in the liver of SHP null mice compared with that of wildtype mice. Overall, our results suggest that the ATM-AMP-activated protein kinase-SHP network, as a novel mechanism for regulating hepatic glucose homeostasis via a GH-dependent pathway, may be a potential therapeutic target for insulin resistance.
Identifier
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<a href="http://doi.org/10.1074/jbc.M112.339887" target="_blank" rel="noreferrer noopener">10.1074/jbc.M112.339887</a>
Format
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Journal Article or Conference Abstract Publication
2012
Ahn S W
AMPK
ataxia-telangiectasia
atm
Biochemistry & Molecular Biology
Chiang J Y L
Choi H S
expression
GLUCOSE
glucose-6-phosphatase gene
Hwang S L
involvement
Journal Article or Conference Abstract Publication
Journal of Biological Chemistry
Kim D K
Kim Y D
Kim Y H
Lee C H
Lee I K
Lee J M
Li T G
metformin
protein kinase
SHP