The transcription activator SREBP-1c (sterol-regulatory-element-binding protein-1c) is induced by insulin in the liver and is considered a master regulator of lipogenic genes such as FASN (fatty acid synthase). The question of whether SREBP-1c is also a mediator of insulin action on the regulatory enzyme of glucose metabolism GCK (glucokinase) is controversial. In the present paper, we induced SREBP-1c to various levels with insulin or the liver X receptor ligand T0901317 in primary hepatocytes and asked if these levels correlated with those of GCK or FASN mRNA expression, using the latter as positive control. Insulin and T0901317 triggered the accumulation of precursor and processed forms of SREBP-1c to similar levels and with comparable kinetics, and both effectors together caused synergistic increases in SREBP-1c protein levels. These effects were accompanied by commensurate elevation of FASN mRNA, notably by a synergistic response to both effectors. By contrast, GCK mRNA was unresponsive to T0901317 and was induced only by insulin. Treatment of hepatocytes with insulin and/or T0901317 resulted in the recruitment of SREBP-1c to the FASN promoter as shown by chromatin immunoprecipitation, whereas SREBP-1c did not bind to the GCK promoter. Lastly, we observed that the glycogen synthase kinase-3 inhibitor SB216763 produced a small increase in SREBP-1c protein level, which was further augmented in the presence of T0901317. The level of FASN mRNA varied in parallel with SREBP-1c, while GCK mRNA was unaffected. Collectively, these results showed that increases in SREBP-1c were neither necessary nor sufficient for GCK induction in hepatocytes, while at the same time they underscored the role of SREBP-1c as a key regulator of FASN.
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Research Article|
September 27 2006
Insulin induction of glucokinase and fatty acid synthase in hepatocytes: analysis of the roles of sterol-regulatory-element-binding protein-1c and liver X receptor
Franck Hansmannel;
Franck Hansmannel
1Department of Cell Physiology and Metabolism, University of Geneva School of Medicine, 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland
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Sylvie Mordier;
Sylvie Mordier
1Department of Cell Physiology and Metabolism, University of Geneva School of Medicine, 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland
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Patrick B. Iynedjian
Patrick B. Iynedjian
1
1Department of Cell Physiology and Metabolism, University of Geneva School of Medicine, 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland
1To whom correspondence should be addressed (email Patrick.Iynedjian@medecine.unige.ch).
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Publisher: Portland Press Ltd
Received:
June 01 2006
Revision Received:
July 07 2006
Accepted:
July 12 2006
Accepted Manuscript online:
July 12 2006
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2006
Biochem J (2006) 399 (2): 275–283.
Article history
Received:
June 01 2006
Revision Received:
July 07 2006
Accepted:
July 12 2006
Accepted Manuscript online:
July 12 2006
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Citation
Franck Hansmannel, Sylvie Mordier, Patrick B. Iynedjian; Insulin induction of glucokinase and fatty acid synthase in hepatocytes: analysis of the roles of sterol-regulatory-element-binding protein-1c and liver X receptor. Biochem J 15 October 2006; 399 (2): 275–283. doi: https://doi.org/10.1042/BJ20060811
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