A STUDY ON CLASSIFICATION OF INHIBITORS OF FATTY ACID TRANSPORT PROTEIN-2 IN CELL

Abstract

Inhibition of uptake of fatty acids in non-adipose tissues seems an attractive mechanism for treatment of lipotoxicity, dyslipidemia and other\nelements related to metabolic syndrome and obesity. Fatty acid transport proteins (FATPs) are bifunctional proteins involved in the uptake and\nactivation of fatty acids by esteri\uf001cation with coenzyme A. To date, only inhibitors speci\uf001c to FATP1 and FATP4 have been identi\uf001ed. Here we\ncharacterize a FATP2-speci\uf001c fatty acid uptake inhibitor, CB5. Identi\uf001ed in a high throughput screening in yeast transformed with humanFATP2,\nCB5 is effective in inhibiting the uptake of fatty acid at low micro-molar ranges in cell lines that are models for intestines, liver, muscle, pancreas\nand adipose tissue with varying potencies.\nInhibition was also speci\uf001c for long and very-long chain fatty acids and not for medium chain fatty acids, which are transported by diffusion.\nFinally, CB5 was effective in protecting the cell lines that are models for liver and pancreas and primary liver cells from lipotoxic effects of\nsaturated fatty acid, palmitic acid. High throughput screening also identi\uf001ed clozapine and chlorpromazine, atypical antipsychotics drugs, as\ninhibitors of FATP2-mediated fatty acid uptake in yeast system. However, atypical antipsychotics were ineffective in inhibiting the uptake of FAanalog C1-BODIPY-C12 in HepG2 cells. They were also ineffective in protecting HepG2 cells from the lipotoxic effects generated by saturated\nfatty acid compared to CB5 that exhibited protection to the cells, demonstrating that they are not effective inhibitors of fatty acid transport\ncompared with CB5.