Fatty acid transport protein-2 inhibitor Grassofermata/CB5 protects cells against lipid accumulation and toxicity.
The inhibition of the fatty acid uptake into non-adipose tissues provides an attractive target for prevention of lipotoxicity leading to obesity-associated non-alcoholic fatty liver disease and type 2 diabetes. Fatty acid transport proteins (FATPs) are bifunctional proteins involved in the uptake and activation of fatty acids by esterification with coenzyme A. Here we characterize Grassofermata/CB5, previously identified as a fatty acid uptake inhibitor directed against HsFATP2. The compound was effective in inhibiting the uptake of fatty acids in the low micro-molar range (IC50 8-11 μM) and prevented palmitate-mediated lipid accumulation and cell death in cell lines that are models for intestines, liver, muscle and pancreas. In adipocytes, uptake inhibition was less effective (IC50 58 μM). Inhibition was specific for long chain fatty acids and was ineffective toward medium chain fatty acids, which are transported by diffusion. Kinetic analysis of Grassofermata-dependent FA transport inhibition verified a non-competitive mechanism. By comparison with Grassofermata, several atypical antipsychotic drugs previously implicated as inhibitors of FA uptake were ineffectual. In mice Grassofermata decreased absorption of (13)C-oleate demonstrating its potential as a therapeutic agent.
Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA.
Nipun
N
Saini
Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA.
Paul N
PN
Black
Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA.
David
D
Montefusco
Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. Electronic address: cdirusso2@unl.edu.
Concetta C
CC
DiRusso
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects*; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005227:Fatty Acids / Q000493:pharmacokinetics; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics*
D005227:Fatty Acids; D011743:Pyrimidines; D003066:Coenzyme A Ligases; C525186:FATP2 protein, mouse
Atypical antipsychotics; FATP2 inhibitor; Fatty acid transport; Lipotoxicity