Pathophysiological regulation of lung function by the free fatty acid receptor FFA4

Prihandoko, R. et al. (2020) Pathophysiological regulation of lung function by the free fatty acid receptor FFA4. Science Translational Medicine, 12(557), eaaw9009. (doi: 10.1126/scitranslmed.aaw9009) (PMID:32817367)

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Abstract

Increased prevalence of inflammatory airway diseases including asthma and chronic obstructive pulmonary disease (COPD) together with inadequate disease control by current frontline treatments means that there is a need to define therapeutic targets for these conditions. Here, we investigate a member of the G protein–coupled receptor family, FFA4, that responds to free circulating fatty acids including dietary omega-3 fatty acids found in fish oils. We show that FFA4, although usually associated with metabolic responses linked with food intake, is expressed in the lung where it is coupled to Gq/11 signaling. Activation of FFA4 by drug-like agonists produced relaxation of murine airway smooth muscle mediated at least in part by the release of the prostaglandin E2 (PGE2) that subsequently acts on EP2 prostanoid receptors. In normal mice, activation of FFA4 resulted in a decrease in lung resistance. In acute and chronic ozone models of pollution-mediated inflammation and house dust mite and cigarette smoke–induced inflammatory disease, FFA4 agonists acted to reduce airway resistance, a response that was absent in mice lacking expression of FFA4. The expression profile of FFA4 in human lung was similar to that observed in mice, and the response to FFA4/FFA1 agonists similarly mediated human airway smooth muscle relaxation ex vivo. Our study provides evidence that pharmacological targeting of lung FFA4, and possibly combined activation of FFA4 and FFA1, has in vivo efficacy and might have therapeutic value in the treatment of bronchoconstriction associated with inflammatory airway diseases such as asthma and COPD.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Alvarez-Curto, Dr Elisa and Dong, Zhaoyang and Alharbi, Abdulrahman Ghali M and Euston, Eloise and Prihandoko, Dr Rudi and Milligan, Professor Graeme and Tobin, Andrew
Authors: Prihandoko, R., Kaur, D., Wiegman, C. H., Alvarez-Curto, E., Donovan, C., Chachi, L., Ulven, T., Tyas, M. R., Euston, E., Dong, Z., Alharbi, A. G. M., Kim, R. Y., Lowe, J. G., Hansbro, P. M., Chung, K. F., Brightling, C. E., Milligan, G., and Tobin, A. B.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Science Translational Medicine
Publisher:American Association for the Advancement of Science
ISSN:1946-6234
ISSN (Online):1946-6242
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Science Translational Medicine 12(557): eaaw9009
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190637GPR120: a G protein-coupled receptor with the potential to regulate insulin secretion and inflammationGraeme MilliganBiotechnology and Biological Sciences Research Council (BBSRC)BB/K019864/1MCSB - Molecular Pharmacology
173610GPR120: a G protein-coupled receptor with the potential to regulate insulin secretion and inflammationAndrew TobinBiotechnology and Biological Sciences Research Council (BBSRC)BB/K019856/2MCSB - Molecular Pharmacology
301391Defining the functional modes of action, and therapeutic potential of targeting, the free fatty acid receptor FFA4 in the lungAndrew TobinMedical Research Council (MRC)MR/R00305X/1Institute of Molecular, Cell & Systems Biology