Oleoylethanolamine and palmitoylethanolamine modulate intestinal permeability in vitro via TRPV1 and PPARα.
Cannabinoids modulate intestinal permeability through cannabinoid receptor 1 (CB1). The endocannabinoid-like compounds oleoylethanolamine (OEA) and palmitoylethanolamine (PEA) play an important role in digestive regulation, and we hypothesized they would also modulate intestinal permeability. Transepithelial electrical resistance (TEER) was measured in human Caco-2 cells to assess permeability after application of OEA and PEA and relevant antagonists. Cells treated with OEA and PEA were stained for cytoskeletal F-actin changes and lysed for immunoassay. OEA and PEA were measured by liquid chromatography-tandem mass spectrometry. OEA (applied apically, logEC50-5.4) and PEA (basolaterally, logEC50-4.9; apically logEC50-5.3) increased Caco-2 resistance by 20-30% via transient receptor potential vanilloid (TRPV)-1 and peroxisome proliferator-activated receptor (PPAR)-α. Preventing their degradation (by inhibiting fatty acid amide hydrolase) enhanced the effects of OEA and PEA. OEA and PEA induced cytoskeletal changes and activated focal adhesion kinase and ERKs 1/2, and decreased Src kinases and aquaporins 3 and 4. In Caco-2 cells treated with IFNγ and TNFα, OEA (via TRPV1) and PEA (via PPARα) prevented or reversed the cytokine-induced increased permeability compared to vehicle (0.1% ethanol). PEA (basolateral) also reversed increased permeability when added 48 or 72 h after cytokines (P < 0.001, via PPARα). Cellular and secreted levels of OEA and PEA (P < 0.001-0.001) were increased in response to inflammatory mediators. OEA and PEA have endogenous roles and potential therapeutic applications in conditions of intestinal hyperpermeability and inflammation.-Karwad, M. A., Macpherson, T., Wang, B., Theophilidou, E., Sarmad, S., Barrett, D. A., Larvin, M., Wright, K. L., Lund, J. N., O'Sullivan, S. E. Oleoylethanolamine and palmitoylethanolamine modulate intestinal permeability in vitro via TRPV1 and PPARα.
School of Medicine, Royal Derby Hospital, University of Nottingham, Nottingham, United Kingdom.
Mustafa A
MA
Karwad
Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, United Kingdom.
Tara
T
Macpherson
Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, United Kingdom.
Bo
B
Wang
School of Medicine, Royal Derby Hospital, University of Nottingham, Nottingham, United Kingdom.
Elena
E
Theophilidou
Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom; and.
Sarir
S
Sarmad
Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom; and.
David A
DA
Barrett
Graduate Entry Medical School, University of Limerick, Limerick, Ireland.|Health Research Institute, University of Limerick, Limerick, Ireland.
Michael
M
Larvin
Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, United Kingdom.
Karen L
KL
Wright
School of Medicine, Royal Derby Hospital, University of Nottingham, Nottingham, United Kingdom.
Jonathan N
JN
Lund
School of Medicine, Royal Derby Hospital, University of Nottingham, Nottingham, United Kingdom; saoirse.osullivan@nottingham.ac.uk.
Saoirse E
SE
O'Sullivan
D000577:Amides; D018938:Caco-2 Cells; D016207:Cytokines; D003599:Cytoskeleton; D004983:Ethanolamines / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007422:Intestines / Q000187:drug effects; D009829:Oleic Acids / Q000494:pharmacology*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D010169:Palmitic Acids / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects; D015398:Signal Transduction; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*
D000577:Amides; D016207:Cytokines; D004983:Ethanolamines; D009829:Oleic Acids; C440229:Oleylethanolamide; D047493:PPAR alpha; D010169:Palmitic Acids; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C005958:palmidrol
cannabinoid; gut; nuclear receptor