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 esterication with coenzyme A. To date, only inhibitors specic to FATP1 and FATP4 have been identied. Here we
characterize a FATP2-specic fatty acid uptake inhibitor, CB5. Identied 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 specic 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 identied 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.
High-throughput screening for fatty acid uptake inhibitors in humanized yeast identifies atypical antipsychotic drugs that cause dyslipidemias