LXR (liver X receptor) and PPARα (peroxisome-proliferator-activated receptor α) are nuclear receptors that control the expression of genes involved in glucose and lipid homoeostasis. Using wild-type and PPARα-null mice fed on an LXR-agonist-supplemented diet, the present study analysed the impact of pharmacological LXR activation on the expression of metabolically important genes in skeletal muscle, testing the hypothesis that LXR activation can modulate PPAR action in skeletal muscle in a manner dependent on nutritional status. In the fed state, LXR activation promoted a gene profile favouring lipid storage and glucose oxidation, increasing SCD1 (stearoyl-CoA desaturase 1) expression and down-regulating PGC-1α (PPARγ co-activator-1α) and PDK4 (pyruvate dehydrogenase kinase 4) expression. PPARα deficiency enhanced LXR stimulation of SCD1 expression, and facilitated elevated SREBP-1 (sterol-regulatory-element-binding protein-1) expression. However, LXR-mediated down-regulation of PGC-1α and PDK4 was opposed and reversed by PPARα deficiency. During fasting, prior LXR activation augmented PPARα signalling to heighten FA (fatty acid) oxidation and decrease glucose oxidation by augmenting fasting-induced up-regulation of PGC-1α and PDK4 expression, effects opposed by PPARα deficiency. Starvation-induced down-regulation of SCD1 expression was opposed by antecedent LXR activation in wild-type mice, an effect enhanced further by PPARα deficiency, which may elicit increased channelling of FA into triacylglycerol to limit lipotoxicity. Our results also identified potential regulatory links between the protein deacetylases SIRT1 (sirtuin 1) and SIRT3 and PDK4 expression in muscle from fasted mice, with a requirement for PPARα. In summary, we therefore propose that a LXR–PPARα signalling axis acts as a metabolostatic regulatory mechanism to optimize substrate selection and disposition in skeletal muscle according to metabolic requirement.
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August 2011
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Research Article|
July 13 2011
PPARα–LXR as a novel metabolostatic signalling axis in skeletal muscle that acts to optimize substrate selection in response to nutrient status
Paul W. Caton;
Paul W. Caton
1
*Centre for Diabetes, Blizard Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, U.K.
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Mark J. Holness;
Mark J. Holness
1
*Centre for Diabetes, Blizard Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, U.K.
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David Bishop-Bailey;
David Bishop-Bailey
†Department of Translational Medicine and Therapeutics, William Harvey Research Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, U.K.
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Mary C. Sugden
Mary C. Sugden
2
*Centre for Diabetes, Blizard Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, U.K.
2To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
April 18 2011
Accepted:
May 24 2011
Accepted Manuscript online:
May 24 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 437 (3): 521–530.
Article history
Received:
April 18 2011
Accepted:
May 24 2011
Accepted Manuscript online:
May 24 2011
Citation
Paul W. Caton, Mark J. Holness, David Bishop-Bailey, Mary C. Sugden; PPARα–LXR as a novel metabolostatic signalling axis in skeletal muscle that acts to optimize substrate selection in response to nutrient status. Biochem J 1 August 2011; 437 (3): 521–530. doi: https://doi.org/10.1042/BJ20110702
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