High-throughput screening for fatty acid uptake inhibitors in humanized yeast identifies atypical antipsychotic drugs that cause dyslipidemias.
Fatty acids are implicated in the development of dyslipidemias, leading to type 2 diabetes and cardiovascular disease. We used a standardized small compound library to screen humanized yeast to identify compounds that inhibit fatty acid transport protein (FATP)-mediated fatty acid uptake into cells. This screening procedure used live yeast cells expressing human FATP2 to identify small compounds that reduced the import of a fluorescent fatty acid analog, 4,4-difluoro-5-methyl-4-bora-3a,4a-diaza-s-indacene-3-dodecanoic acid (C(1)-BODIPY-C(12)). The library used consisted of 2,080 compounds with known biological activities. Of these, approximately 1.8% reduced cell-associated C(1)-BODIPY-C(12) fluorescence and were selected as potential inhibitors of human FATP2-mediated fatty acid uptake. Based on secondary screens, 28 compounds were selected as potential fatty acid uptake inhibitors. Some compounds fell into four groups with similar structural features. The largest group was structurally related to a family of tricyclic, phenothiazine-derived drugs used to treat schizophrenia and related psychiatric disorders, which are also known to cause metabolic side effects, including hypertriglyceridemia. Potential hit compounds were studied for specificity of interaction with human FATP and efficacy in human Caco-2 cells. This study validates this screening system as useful to assess the impact of drugs in preclinical screening for fatty acid uptake.
Li
Hong
H
Center for Metabolic Disease, Ordway Research Institute, Inc., Albany Medical College, Albany, NY 12208, USA.
Black
Paul N
PN
Chokshi
Aalap
A
Sandoval-Alvarez
Angel
A
Vatsyayan
Ravi
R
Sealls
Whitney
W
DiRusso
Concetta C
CC
D014150:Antipsychotic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001692:Biological Transport; D018938:Caco-2 Cells; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D050171:Dyslipidemias / Q000139:chemically induced / Q000378:metabolism; D050612:Fatty Acid Transport Proteins / Q000037:antagonists & inhibitors*; D005227:Fatty Acids / Q000378:metabolism*; D005632:Fructose; D006801:Humans; D012441:Saccharomyces cerevisiae; D054852:Small Molecule Libraries
D014150:Antipsychotic Agents; D050612:Fatty Acid Transport Proteins; D005227:Fatty Acids; D054852:Small Molecule Libraries; D005632:Fructose