| Identification and characterization of small compound inhibitors of human FATP2. | |
| | |
MedLine Citation:
|
PMID: 19913517 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
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. |
| | |
Authors:
|
Angel Sandoval; Aalap Chokshi; Elliot D Jesch; Paul N Black; Concetta C Dirusso |
Related Documents
:
|
9492907 - Volume-activated taurine efflux from the in situ perfused lactating rat mammary gland. 638147 - Transport of l-methionine in human diploid fibroblast strain wi38. 14977407 - Molecular and integrative physiology of intestinal peptide transport. 3612557 - Transport of benzylpenicillin by the rat choroid plexus in vitro. 8076167 - Variation in the concentration of long chain free fatty acids in equine plasma over 24 ... 10911767 - Ethanol with a mixed meal increases postprandial triacylglycerol but decreases postpran... |
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: 2013-03-14 |
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. |
Affiliation:
|
Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0664, United States. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
3T3-L1 Cells Animals 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 Humans Mice Structure-Activity Relationship |
| Grant Support | |
ID/Acronym/Agency:
|
DK07076/DK/NIDDK NIH HHS; GM56850/GM/NIGMS NIH HHS; R01 DK071076/DK/NIDDK NIH HHS; R01 DK071076-03/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Fatty Acid Transport Proteins; 0/Fatty Acids; EC 6.2.1.-/Coenzyme A Ligases |
| Comments/Corrections | |
Erratum In:
|
Biochem Pharmacol. 2012 Aug 15;84(4):580 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Investigating the interaction of McN-A-343 with the M2 muscarinic receptor using its nitrogen mustar...
Next Document: Therapeutic benefits of human mesenchymal stem cells derived from bone marrow after global cerebral ...