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 elements related to metabolic syndrome and obesity. Fatty acid transport proteins (FATPs) are bifunctional proteins involved in the uptake and activation of fatty acids by esterication with coenzyme A. To date, only inhibitors specic to FATP1 and FATP4 have been identied. Here we characterize a FATP2-specic fatty acid uptake inhibitor, CB5. Identied in a high throughput screening in yeast transformed with humanFATP2, CB5 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 and adipose tissue with varying potencies. Inhibition was also specic for long and very-long chain fatty acids and not for medium chain fatty acids, which are transported by diffusion. Finally, CB5 was effective in protecting the cell lines that are models for liver and pancreas and primary liver cells from lipotoxic effects of saturated fatty acid, palmitic acid. High throughput screening also identied clozapine and chlorpromazine, atypical antipsychotics drugs, as inhibitors 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 fatty acid compared to CB5 that exhibited protection to the cells, demonstrating that they are not effective inhibitors of fatty acid transport compared with CB5.