Ghrelin, an endogenous ligand of the GH (growth hormone) secretagogue receptor, influences many metabolic processes including GH secretion, food intake, energy balance, insulin secretion and adipogenesis. Although ghrelin exhibits a variety of biological functions, the mechanism by which ghrelin expression is regulated is unknown. Ghrelin is expressed in the gastrointestinal tract, predominantly in the stomach, as is KLF4 (Krüppel-like factor 4). Therefore we investigated whether ghrelin expression is associated with KLF4, and found that the tissue distribution of ghrelin corresponded with that of KLF4. Furthermore, treatment with butyrate, an inducer of KLF4 expression, stimulated ghrelin expression, and fasting, which induces ghrelin expression, also increased KLF4 expression, suggesting that ghrelin expression is associated with KLF4. Then, we investigated the effects of KLF4 on the human ghrelin-promoter activity and identified a KLF4-responsive region in the promoter. KLF4 expression specifically stimulated human ghrelin-promoter activity in a dose-dependent manner in human gastric-cancer AGS cells. However, this effect was not seen in response to a mutant KLF4 construct. Transfection studies using mutant constructs containing 5′-deletions in the human ghrelin promoter revealed that the KLF4-responsive element is located between −1228 and −1105. Electrophoretic mobility shift assays using oligonucleotides containing −1165/−1146 revealed the binding of KLF4 to the human ghrelin promoter. Finally, deletion of the −1165/−1146 region abrogated KLF4-induced transactivation of the ghrelin promoter. Collectively, these results indicate that KLF4 positively regulates human ghrelin expression via binding to a KLF-responsive region in the promoter.
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Research Article|
May 27 2009
KLF4 positively regulates human ghrelin expression
Hyo Jung Lee;
Hyo Jung Lee
*Division of Metabolic Disease, Department of Biomedical Science, National Institute of Health, 5 Nokbun-dong, Eunpyung-gu, Seoul 122-701, South Korea
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Young Mi Kang;
Young Mi Kang
†Pusan National University School of Oriental Medicine, 30 Jangjeon-dong, Geumjeong-gu, Pusan 609-735, South Korea
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Chang Suk Moon;
Chang Suk Moon
*Division of Metabolic Disease, Department of Biomedical Science, National Institute of Health, 5 Nokbun-dong, Eunpyung-gu, Seoul 122-701, South Korea
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Myung Kuk Joe;
Myung Kuk Joe
*Division of Metabolic Disease, Department of Biomedical Science, National Institute of Health, 5 Nokbun-dong, Eunpyung-gu, Seoul 122-701, South Korea
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Joo Hyun Lim;
Joo Hyun Lim
*Division of Metabolic Disease, Department of Biomedical Science, National Institute of Health, 5 Nokbun-dong, Eunpyung-gu, Seoul 122-701, South Korea
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Young Ho Suh;
Young Ho Suh
*Division of Metabolic Disease, Department of Biomedical Science, National Institute of Health, 5 Nokbun-dong, Eunpyung-gu, Seoul 122-701, South Korea
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Jihyun Song;
Jihyun Song
*Division of Metabolic Disease, Department of Biomedical Science, National Institute of Health, 5 Nokbun-dong, Eunpyung-gu, Seoul 122-701, South Korea
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Myeong Ho Jung
Myeong Ho Jung
1
*Division of Metabolic Disease, Department of Biomedical Science, National Institute of Health, 5 Nokbun-dong, Eunpyung-gu, Seoul 122-701, South Korea
†Pusan National University School of Oriental Medicine, 30 Jangjeon-dong, Geumjeong-gu, Pusan 609-735, South Korea
1To whom correspondence should be addressed (email jung0603@pusan.ac.kr).
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Publisher: Portland Press Ltd
Received:
September 12 2008
Revision Received:
March 26 2009
Accepted:
March 27 2009
Accepted Manuscript online:
March 27 2009
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem J (2009) 420 (3): 403–411.
Article history
Received:
September 12 2008
Revision Received:
March 26 2009
Accepted:
March 27 2009
Accepted Manuscript online:
March 27 2009
Citation
Hyo Jung Lee, Young Mi Kang, Chang Suk Moon, Myung Kuk Joe, Joo Hyun Lim, Young Ho Suh, Jihyun Song, Myeong Ho Jung; KLF4 positively regulates human ghrelin expression. Biochem J 15 June 2009; 420 (3): 403–411. doi: https://doi.org/10.1042/BJ20081850
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