title: The blood-brain barrier fatty acid transport protein 1 (FATP1/SLC27A1) supplies docosahexaenoic acid to the brain, and insulin facilitates transport.
abstract: We purposed to clarify the contribution of fatty acid transport protein 1 (FATP1/SLC 27A1) to the supply of docosahexaenoic acid (DHA) to the brain across the blood-brain barrier in this study. Transport experiments showed that the uptake rate of [14C]-DHA in human FATP1-expressing HEK293 cells was significantly greater than that in empty vector-transfected (mock) HEK293 cells. The steady-state intracellular DHA concentration was nearly 2-fold smaller in FATP1-expressing than in mock cells, suggesting that FATP1 works as not only an influx, but also an efflux transporter for DHA. [14C]-DHA uptake by a human cerebral microvascular endothelial cell line (hCMEC/D3) increased in a time-dependent manner, and was inhibited by unlabeled DHA and a known FATP1 substrate, oleic acid. Knock-down of FATP1 in hCMEC/D3 cells with specific siRNA showed that FATP1-mediated uptake accounts for 59.2-73.0% of total [14C]-DHA uptake by the cells. Insulin treatment for 30 min induced translocation of FATP1 protein to the plasma membrane in hCMEC/D3 cells and enhanced [14C]-DHA uptake. Immunohistochemical analysis of mouse brain sections showed that FATP1 protein is preferentially localized at the basal membrane of brain microvessel endothelial cells. We found that two neuroprotective substances, taurine and biotin, in addition to DHA, undergo FATP1-mediated efflux. Overall, our results suggest that FATP1 localized at the basal membrane of brain microvessels contributes to the transport of DHA, taurine and biotin into the brain, and insulin rapidly increases DHA supply to the brain by promoting translocation of FATP1 to the membrane. Read the Editorial Comment for this article on page 324.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan.
authors.forename: Yusuke
authors.identifier: 0000-0002-0402-8137
authors.initials: Y
authors.lastname: Ochiai
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchida
authors.affiliation: Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.|Japan Agency for Medical Research and Development (AMED) CREST, Tokyo, Japan.
authors.forename: Sumio
authors.initials: S
authors.lastname: Ohtsuki
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Tachikawa
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan.
authors.forename: Sanshiro
authors.initials: S
authors.lastname: Aizawa
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Terasaki
mesh_terms: D000818:Animals; D001710:Biotin / Q000378:metabolism; D018916:Blood-Aqueous Barrier / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects*; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D050612:Fatty Acid Transport Proteins / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019301:Oleic Acid / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D013654:Taurine / Q000378:metabolism
chemical_list: D050612:Fatty Acid Transport Proteins; D007328:Insulin; D034741:RNA, Small Interfering; C493569:Slc27a1 protein, mouse; D013654:Taurine; D004281:Docosahexaenoic Acids; D019301:Oleic Acid; D001710:Biotin
keywords: FATP1; basal localization; blood-brain barrier; docosahexaenoic acid; insulin; neuroprotective compounds