Submitted on June 14, 2007
Revised on October 4, 2007
Accepted on October 10, 2007
High throughput screening for fatty acid uptake inhibitors in humanized yeast identifies atypical antipsychotics that cause dyslipidemias
Hong Li, Paul N. Black, Aalap Chokshi, Angel Sandoval-Alvarez, Ravi Vatsyayan, Whitney Sealls, and Concetta C. DiRusso
Center for Metabolic Disease, Ordway Research Inst., Inc., Albany, NY 12208
Corresponding Author: cdirusso{at}ordwayresearch.org
Fatty acids are implicated in the development of dyslipidemias, leading to type 2 diabetes and cardiovascular disease. We employed 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 employed live yeast cells expressing human FATP2 to identify small compounds that reduced the import of a fluorescent fatty acid analogue 4,4-difluoro-5-methyl-4-bora-3a,4a-diaza-s-indacene-3-dodecanoic acid (C1-BODIPY-C12). The library used consisted of 2,080 compounds with known biological activities. Of these, approximately 1.8% reduced cell associated C1-BODIPY-C12 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 4 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 hsFATP and efficacy in human Caco-2 cells. This study validates this screening system useful to assess the impact of drugs in preclinical screening on fatty acid uptake.
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