Document Detail

Identification and characterization of small compound inhibitors of human FATP2.
MedLine Citation:
PMID:  19913517     Owner:  NLM     Status:  MEDLINE    
Fatty acid transport proteins (FATPs) are bifunctional proteins, which transport long chain fatty acids into cells and activate very long chain fatty acids by esterification with coenzyme A. In an effort to understand the linkage between cellular fatty acid transport and the pathology associated with excessive accumulation of exogenous fatty acids, we targeted FATP-mediated fatty acid transport in a high throughput screen of more than 100,000 small diverse chemical compounds in yeast expressing human FATP2 (hsFATP2). Compounds were selected for their ability to depress the transport of the fluorescent long chain fatty acid analogue, C(1)-BODIPY-C(12). Among 234 hits identified in the primary screen, 5 compounds, each representative of a structural class, were further characterized in the human Caco-2 and HepG2 cell lines, each of which normally expresses FATP2, and in 3T3-L1 adipocytes, which do not. These compounds were effective in inhibiting uptake with IC(50)s in the low micromolar range in both Caco-2 and HepG2 cells. Inhibition of transport was highly specific for fatty acids and there were no effects of these compounds on cell viability, trans-epithelial electrical resistance, glucose transport, or long chain acyl-CoA synthetase activity. The compounds were less effective when tested in 3T3-L1 adipocytes suggesting selectivity of inhibition. These results suggest fatty acid transport can be inhibited in a FATP-specific manner without causing cellular toxicity.
Angel Sandoval; Aalap Chokshi; Elliot D Jesch; Paul N Black; Concetta C Dirusso
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-11-11
Journal Detail:
Title:  Biochemical pharmacology     Volume:  79     ISSN:  1873-2968     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-02-01     Completed Date:  2010-03-02     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  990-9     Citation Subset:  IM    
Copyright Information:
Copyright 2009 Elsevier Inc. All rights reserved.
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MeSH Terms
3T3-L1 Cells
Biological Transport / drug effects
Caco-2 Cells
Coenzyme A Ligases / metabolism
Dose-Response Relationship, Drug
Fatty Acid Transport Proteins / antagonists & inhibitors*
Fatty Acids / metabolism
Hep G2 Cells
High-Throughput Screening Assays
Structure-Activity Relationship
Grant Support
Reg. No./Substance:
0/Fatty Acid Transport Proteins; 0/Fatty Acids; EC 6.2.1.-/Coenzyme A Ligases
Erratum In:
Biochem Pharmacol. 2012 Aug 15;84(4):580

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