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Nitrogen oxides and the control of fatty acid oxidation in hypoxia

Supervisor: Andrew Murray

Our research focuses on energy metabolism in tissues such as heart, liver and skeletal muscle, which are dependent upon a supply of oxygen in order to maintain normal function at the mitochondria. A major interest is how metabolism is altered in these tissues in the context of hypoxia e.g. at high-altitude or in certain diseases, where oxygen delivery to the tissues is challenged, resulting in adverse effects on cellular function. Populations that have been resident at high-altitude (e.g. in Tibet and the Andes) show some protection against chronic hypobaric hypoxia, for instance, whilst in lowland natives muscle energetic reserve falls at altitude, energetics are maintained or even enhanced in highlanders. Recent genetic evidence from these populations has hinted at potential mechanisms, which may include suppression of hypoxia-sensing pathways and increased production of nitric oxide. We have worked extensively with lowlanders and Nepalese Sherpas at altitude to investigate the roles that nitrogen oxides play in protecting humans against lifelong hypoxia and oxidative stress, and the implications for a healthy diet. We have found that in Sherpas, fatty acid oxidation pathways are reconfigured, such that mitochondrial oxygen efficiency is enhanced, whilst tissues are protected against the potentially-harmful accumulation of lipid intermediates. This work therefore has implications for metabolic diseases, such as obesity and diabetes, where fatty acid availability outweighs tissue oxidation capacity. Dietary nitrate supplementation, via increased consumption of leafy-green vegetables, provides one possible route by which NO levels can be elevated and such protection might therefore conferred upon native lowlanders. Consequently, we have used cell culture systems and animal models to further probe the effects of nitrate on oxygen delivery and utilisation. This project will combine further studies on humans at high-altitude with similar mechanistic approaches, and a particular focus on the regulation of fatty acid metabolism pathways.

Relevant references

DZ Levett, et al. Acclimatization of skeletal muscle mitochondria to high-altitude hypoxia during an ascent of Everest. FASEB J. 26:1431-41, 2012.

T Ashmore, et al. Nitrate enhances skeletal muscle fatty acid oxidation via a nitric oxide-cGMP-PPAR-mediated mechanism. BMC Biol. 13: 110, 2015.

 TS Simonson, et al. Genetic evidence for high-altitude adaptation in Tibet. Science. 329:72-5, 2010.

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