Cellular uptake of fatty acids driven by the ER-localized acyl-CoA synthetase FATP4.
Long-chain fatty acids are important metabolites for the generation of energy and the biosynthesis of lipids. The molecular mechanism of their cellular uptake has remained controversial. The fatty acid transport protein (FATP) family has been named according to its proposed function in mediating this process at the plasma membrane. Here, we show that FATP4 is in fact localized to the endoplasmic reticulum and not the plasma membrane as reported previously. Quantitative analysis confirms the positive correlation between expression of FATP4 and uptake of fatty acids. However, this is dependent on the enzymatic activity of FATP4, catalyzing the esterification of fatty acids with CoA. Monitoring fatty acid uptake at the single-cell level demonstrates that the ER localization of FATP4 is sufficient to drive transport of fatty acids. Expression of a mitochondrial acyl-CoA synthetase also enhances fatty acid uptake, suggesting a general relevance for this mechanism. Our results imply that cellular uptake of fatty acids can be regulated by intracellular acyl-CoA synthetases. We propose that the enzyme FATP4 drives fatty acid uptake indirectly by esterification. It is not a transporter protein involved in fatty acid translocation at the plasma membrane.
Milger
Katrin
K
Department of Gastroenterology, Im Neuenheimer Feld 345, University of Heidelberg, 69120 Heidelberg, Germany.
Herrmann
Thomas
T
Becker
Christiane
C
Gotthardt
Daniel
D
Zickwolf
Jelena
J
Ehehalt
Robert
R
Watkins
Paul A
PA
Stremmel
Wolfgang
W
Füllekrug
Joachim
J
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001693:Biological Transport, Active; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003065:Coenzyme A / Q000378:metabolism; D003066:Coenzyme A Ligases / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D050612:Fatty Acid Transport Proteins / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism; D009154:Mutation; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D003065:Coenzyme A; D003066:Coenzyme A Ligases; D050612:Fatty Acid Transport Proteins; D005227:Fatty Acids; D024101:Mitochondrial Proteins; D011993:Recombinant Fusion Proteins; C499318:Ascl1 protein, rat; C493572:Slc27a4 protein, mouse