The free fatty acid receptor 1 promotes airway smooth muscle cell proliferation through MEK/ERK and PI3K/Akt signaling pathways

Atsuko Matoba, Nao Matsuyama, Sumire Shibata, Eiji Masaki, Charles W. Emala, Kentaro Mizuta

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)


Obesity is a risk factor for asthma and influences airway hyperresponsiveness, which is in part modulated by airway smooth muscle proliferative remodeling. Plasma free fatty acids (FFAs) levels are elevated in obese individuals, and long-chain FFAs act as endogenous ligands for the free fatty acid receptor 1 (FFAR1), which couples to both Gq and Gi proteins. We examined whether stimulation of FFAR1 induces airway smooth muscle cell proliferation through classical MEK/ERK and/or phosphoinositide 3-kinase (PI3K)/Akt signaling pathways. The long-chain FFAs (oleic acid and linoleic acid) and a FFAR1 agonist (GW9508) induced human airway smooth muscle (HASM) cell proliferation, which was inhibited by the MEK inhibitor U0126 and the PI3K inhibitor LY294002. The long-chain FFAs and GW9508 increased phosphorylation of ERK, Akt, and p70S6K in HASM cells and freshly isolated rat airway smooth muscle. Downregulation of FFAR1 in HASM cells by siRNA significantly attenuated oleic acid-induced phosphorylation of ERK and Akt. Oleic acid-induced ERK phosphorylation was blocked by either the Gαi-protein inhibitor pertussis toxin or U0126 and was partially inhibited by either the Gαq-specific inhibitor YM-254890 or the Gβγ signaling inhibitor gallein. Oleic acid significantly inhibited forskolinstimulated cAMP activity, which was attenuated by pertussis toxin. Akt phosphorylation was inhibited by pertussis toxin, the ras inhibitor manumycin A, the Src inhibitor PP1, or LY294002. Phosphorylation of p70S6K by oleic acid or GW9508 was significantly inhibited by LY294002, U0126, and the mammalian target of rapamycin (mTOR) inhibitor rapamycin. In conclusion, the FFAR1 promoted airway smooth muscle cell proliferation and p70S6K phosphorylation through MEK/ERK and PI3K/Akt signaling pathways.

Original languageEnglish
Pages (from-to)L333-L348
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number3
Publication statusPublished - 2018 Mar


  • Airway remodeling
  • Cell proliferation
  • FFAR1
  • Free fatty acid
  • G protein-coupled receptor

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology


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