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)

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 Meshal 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 > School of Molecular Biosciences; 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

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
190637		GPR120: a G protein-coupled receptor with the potential to regulate insulin secretion and inflammation	Graeme Milligan	Biotechnology and Biological Sciences Research Council (BBSRC)	BB/K019864/1	MCSB - Molecular Pharmacology
173610		GPR120: a G protein-coupled receptor with the potential to regulate insulin secretion and inflammation	Andrew Tobin	Biotechnology and Biological Sciences Research Council (BBSRC)	BB/K019856/2	MCSB - Molecular Pharmacology
301391		Defining the functional modes of action, and therapeutic potential of targeting, the free fatty acid receptor FFA4 in the lung	Andrew Tobin	Medical Research Council (MRC)	MR/R00305X/1	Institute of Molecular, Cell & Systems Biology