The enhanced synthesis of fatty acids in the liver and adipose tissue in response to insulin is critically dependent on the transcription factor SREBP-1c (sterol-regulatory-element-binding protein 1c). Insulin increases the expression of the SREBP-1c gene in intact liver and in hepatocytes cultured in vitro. To learn the mechanism of this stimulation, we analysed the activation of the rat SREBP-1c promoter and its truncated or mutated congeners driving a luciferase reporter gene in transiently transfected rat hepatocytes. The rat SREBP-1c promoter contains binding sites for LXR (liver X receptor), Sp1, NF-Y (nuclear factor-Y) and SREBP itself. We have found that each of these sites is required for the full stimulatory response of the SREBP-1c promoter to insulin. Mutation of either the putative LXREs (LXR response elements) or the SRE (sterol response element) in the proximal SREBP-1c promoter reduced the stimulatory effect of insulin by about 50%. Insulin and the LXR agonist TO901317 increased the association of SREBP-1 with the SREBP-1c promoter. Ectopic expression of LXRα or SREBP-1c increased activity of the SREBP-1c promoter, and this effect is further enhanced by insulin. The Sp1 and NF-Y sites adjacent to the SRE are also required for full activation of the SREBP-1c promoter by insulin. We propose that the combined actions of the SRE, LXREs, Sp1 and NF-Y elements constitute an insulin-responsive cis-acting unit of the SREBP-1c gene in the liver.
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Research Article|
December 14 2004
Insulin activates the rat sterol-regulatory-element-binding protein 1c (SREBP-1c) promoter through the combinatorial actions of SREBP, LXR, Sp-1 and NF-Y cis-acting elements
Lauren M. CAGEN;
Lauren M. CAGEN
1
*Departments of Pharmacology and Medicine, The University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN 38163, U.S.A.
1To whom correspondence should be addressed (email lcagen@utmem.edu).
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Xiong DENG;
Xiong DENG
*Departments of Pharmacology and Medicine, The University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN 38163, U.S.A.
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Henry G. WILCOX;
Henry G. WILCOX
*Departments of Pharmacology and Medicine, The University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN 38163, U.S.A.
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Edwards A. PARK;
Edwards A. PARK
*Departments of Pharmacology and Medicine, The University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN 38163, U.S.A.
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Rajendra RAGHOW;
Rajendra RAGHOW
*Departments of Pharmacology and Medicine, The University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN 38163, U.S.A.
†Department of Veterans Affairs Medical Center, 1030 Jefferson Avenue, Memphis, TN 38104, U.S.A.
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Marshall B. ELAM
Marshall B. ELAM
*Departments of Pharmacology and Medicine, The University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN 38163, U.S.A.
†Department of Veterans Affairs Medical Center, 1030 Jefferson Avenue, Memphis, TN 38104, U.S.A.
‡Division of Clinical Pharmacology, The University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN 38163, U.S.A.
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Publisher: Portland Press Ltd
Received:
January 28 2004
Revision Received:
July 28 2004
Accepted:
August 26 2004
Accepted Manuscript online:
August 26 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 385 (1): 207–216.
Article history
Received:
January 28 2004
Revision Received:
July 28 2004
Accepted:
August 26 2004
Accepted Manuscript online:
August 26 2004
Citation
Lauren M. CAGEN, Xiong DENG, Henry G. WILCOX, Edwards A. PARK, Rajendra RAGHOW, Marshall B. ELAM; Insulin activates the rat sterol-regulatory-element-binding protein 1c (SREBP-1c) promoter through the combinatorial actions of SREBP, LXR, Sp-1 and NF-Y cis-acting elements. Biochem J 1 January 2005; 385 (1): 207–216. doi: https://doi.org/10.1042/BJ20040162
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