Iron Reduces the Trafficking of Fatty Acids from Human Immortalised Brain Microvascular Endothelial Cells Through Modulation of Fatty Acid Transport Protein 1 (FATP1/SLC27A1)

• Published in: Pharmaceutical research 2024-08, Vol.41 (8), p.1631-1648
• Main Authors: Supti, Showmika T., Koehn, Liam M., Newman, Stephanie A., Pan, Yijun, Nicolazzo, Joseph A.
• Format: Article
• Language: English
• Subjects: Advertising executives; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; Biochemistry; Biological Transport - drug effects; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Blood levels; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Brain; Brain - drug effects; Brain - metabolism; Cell Line; Docosahexaenoic acid; Docosahexaenoic Acids - pharmacology; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelium; Ethylenediaminetetraacetic acid; Fatty Acid Transport Proteins - genetics; Fatty Acid Transport Proteins - metabolism; Fatty acid-binding protein; Fatty Acid-Binding Proteins - genetics; Fatty Acid-Binding Proteins - metabolism; Fatty acids; Fatty Acids - metabolism; Ferric Compounds; Gene expression; Humans; Iron; Iron - metabolism; Iron compounds; Medical Law; Microvasculature; Microvessels - cytology; Microvessels - drug effects; Microvessels - metabolism; Monounsaturated fatty acids; mRNA; Neurodegenerative diseases; Oleic acid; Omega-3 fatty acids; Original Research Article; Pharmacology/Toxicology; Pharmacy; Protein binding; Protein transport; Proteins; Quaternary Ammonium Compounds - pharmacology; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; β-Amyloid
• ISSN: 0724-8741; 1573-904X; 1573-904X
• DOI: 10.1007/s11095-024-03743-w

Purpose Alzheimer’s disease (AD) is associated with brain accumulation of amyloid-beta (Aβ) and neurofibrillary tangle formation, in addition to reduced brain docosahexaenoic acid (DHA) and increased brain iron levels. DHA requires access across the blood–brain barrier (BBB) to enter the brain, and iron has been shown to affect the expression and function of a number of BBB transporters. Therefore, this study aimed to assess the effect of iron on the expression and function of fatty acid binding protein 5 (FABP5) and fatty acid transport protein 1 (FATP1), both which mediate brain endothelial cell trafficking of DHA. Methods The mRNA and protein levels of FABP5 and FATP1 in human cerebral microvascular endothelial (hCMEC/D3) cells was assessed by RT-qPCR and Western blot, respectively following ferric ammonium citrate (FAC) treatment (up to 750 µM, 72 h). The function of FABP5 and FATP1 was assessed via uptake and efflux of radiolabelled 3 H-oleic acid and 14 C-DHA. Results FAC (500 µM, 72 h) had no impact on the expression of FABP5 at the protein and mRNA level in hCMEC/D3 cells, which was associated with a lack of effect on the uptake of 14 C-DHA. FAC led to a 19.7% reduction in FATP1 protein abundance in hCMEC/D3 cells with no impact on mRNA levels, and this was associated with up to a 32.6% reduction in efflux of 14 C-DHA. Conclusions These studies demonstrate a role of iron in down-regulating FATP1 protein abundance and function at the BBB, which may have implications on fatty acid access to the brain. Graphical Abstract