GSD-1 (glycogen storage disease type 1) is caused by an inherited defect in glucose-6-phosphatase activity, resulting in a massive accumulation of hepatic glycogen content and an induction of de novo lipogenesis. The chlorogenic acid derivative S4048 is a pharmacological inhibitor of the glucose 6-phosphate transporter, which is part of glucose-6-phosphatase, and allows for mechanistic studies concerning metabolic defects in GSD-1. Treatment of mice with S4048 resulted in an ~60% reduction in blood glucose, increased hepatic glycogen and triacylglycerol (triglyceride) content, and a markedly enhanced hepatic lipogenic gene expression. In mammals, hepatic expression of lipogenic genes is regulated by the co-ordinated action of the transcription factors SREBP (sterol-regulatory-element-binding protein)-1c, LXRα (liver X receptor α) and ChREBP (carbohydrate-response-element-binding protein). Treatment of Lxra−/− mice and Chrebp−/− mice with S4048 demonstrated that ChREBP, but not LXRα, mediates the induction of hepatic lipogenic gene expression in this murine model of GSD-1. Thus ChREBP is an attractive target to alleviate derangements in lipid metabolism observed in patients with GSD-1.
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December 2010
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Research Article|
November 12 2010
Carbohydrate-response-element-binding protein (ChREBP) and not the liver X receptor α (LXRα) mediates elevated hepatic lipogenic gene expression in a mouse model of glycogen storage disease type 1
Aldo Grefhorst
;
*Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
2To whom correspondence should be addressed (email a.grefhorst@med.umcg.nl).
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Marijke Schreurs
;
Marijke Schreurs
1
†Molecular Genetics Section, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Maaike H. Oosterveer
;
Maaike H. Oosterveer
*Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Victor A. Cortés
;
Victor A. Cortés
‡Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, U.S.A.
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Rick Havinga
;
Rick Havinga
*Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Andreas W. Herling
;
Andreas W. Herling
§Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany
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Dirk-Jan Reijngoud
;
Dirk-Jan Reijngoud
∥Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
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Albert K. Groen
;
Albert K. Groen
*Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
∥Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
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Folkert Kuipers
Folkert Kuipers
*Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
∥Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
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Biochem J (2010) 432 (2): 249–254.
Article history
Received:
August 12 2010
Revision Received:
September 13 2010
Accepted:
September 20 2010
Accepted Manuscript online:
September 20 2010
Citation
Aldo Grefhorst, Marijke Schreurs, Maaike H. Oosterveer, Victor A. Cortés, Rick Havinga, Andreas W. Herling, Dirk-Jan Reijngoud, Albert K. Groen, Folkert Kuipers; Carbohydrate-response-element-binding protein (ChREBP) and not the liver X receptor α (LXRα) mediates elevated hepatic lipogenic gene expression in a mouse model of glycogen storage disease type 1. Biochem J 1 December 2010; 432 (2): 249–254. doi: https://doi.org/10.1042/BJ20101225
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