Imperial College London
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DrAndrewCowburn

Faculty of Medicine, National Heart & Lung Institute

Senior Lecturer (Non-Clinical)
 
 
 
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a.cowburn

 
 
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Location

 

535ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Ashmore:2015:10.1186/s12915-015-0221-6,
author = {Ashmore, T and Roberts, LD and Morash, AJ and Kotwica, AO and Finnerty, J and West, JA and Murfitt, SA and Fernandez, BO and Branco, C and Cowburn, AS and Clarke, K and Johnson, RS and Feelisch, M and Griffin, JL and Murray, AJ},
doi = {10.1186/s12915-015-0221-6},
journal = {BMC Biology},
pages = {1--17},
title = {Nitrate enhances skeletal muscle fatty acid oxidation via a nitric oxide-cGMP-PPAR-mediated mechanism},
url = {http://dx.doi.org/10.1186/s12915-015-0221-6},
volume = {13},
year = {2015}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - BackgroundInsulin sensitivity in skeletal muscle is associated with metabolic flexibility, including a high capacity to increase fatty acid (FA) oxidation in response to increased lipid supply. Lipid overload, however, can result in incomplete FA oxidation and accumulation of potentially harmful intermediates where mitochondrial tricarboxylic acid cycle capacity cannot keep pace with rates of β-oxidation. Enhancement of muscle FA oxidation in combination with mitochondrial biogenesis is therefore emerging as a strategy to treat metabolic disease. Dietary inorganic nitrate was recently shown to reverse aspects of the metabolic syndrome in rodents by as yet incompletely defined mechanisms.ResultsHerein, we report that nitrate enhances skeletal muscle FA oxidation in rodents in a dose-dependent manner. We show that nitrate induces FA oxidation through a soluble guanylate cyclase (sGC)/cGMP-mediated PPARβ/δ- and PPARα-dependent mechanism. Enhanced PPARβ/δ and PPARα expression and DNA binding induces expression of FA oxidation enzymes, increasing muscle carnitine and lowering tissue malonyl-CoA concentrations, thereby supporting intra-mitochondrial pathways of FA oxidation and enhancing mitochondrial respiration. At higher doses, nitrate induces mitochondrial biogenesis, further increasing FA oxidation and lowering long-chain FA concentrations. Meanwhile, nitrate did not affect mitochondrial FA oxidation in PPARα−/− mice. In C2C12 myotubes, nitrate increased expression of the PPARα targets Cpt1b, Acadl, Hadh and Ucp3, and enhanced oxidative phosphorylation rates with palmitoyl-carnitine; however, these changes in gene expression and respiration were prevented by inhibition of either sGC or protein kinase G. Elevation of cGMP, via the inhibition of phosphodiesterase 5 by sildenafil, also increased expression of Cpt1b, Acadl and Ucp3, as well as CPT1B protein levels, and further enhanced the effect of nitrate s
AU  - Ashmore,T
AU  - Roberts,LD
AU  - Morash,AJ
AU  - Kotwica,AO
AU  - Finnerty,J
AU  - West,JA
AU  - Murfitt,SA
AU  - Fernandez,BO
AU  - Branco,C
AU  - Cowburn,AS
AU  - Clarke,K
AU  - Johnson,RS
AU  - Feelisch,M
AU  - Griffin,JL
AU  - Murray,AJ
DO  - 10.1186/s12915-015-0221-6
EP  - 17
PY  - 2015///
SN  - 1741-7007
SP  - 1
TI  - Nitrate enhances skeletal muscle fatty acid oxidation via a nitric oxide-cGMP-PPAR-mediated mechanism
T2  - BMC Biology
UR  - http://dx.doi.org/10.1186/s12915-015-0221-6
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000367050600002&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-015-0221-6
UR  - http://hdl.handle.net/10044/1/81719
VL  - 13
ER  -
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