A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs

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Abstract

Fatty acids, which are essential nutritional components, are also involved in cardiovascular and metabolic diseases. Here we report a human cell surface receptor that we name free fatty acid receptor (FFAR), because it is specifically activated by medium to long-chain free fatty acids. The receptor belongs to the class of seven-transmembrane, G-protein coupled receptors (GPCRs) and also mediates responses to antidiabetic drugs of the thiazolidinedione type. It is expressed in skeletal muscle, heart, liver, and pancreatic β-cells. Stimulation of FFAR increases the intracellular calcium concentration in cells expressing the receptor in a native (pancreatic β-cell line) or in a recombinant form. In view of the nature of the activating substances, their physiological role in the body, and the tissue distribution of FFAR we suggest the term “nutrient sensing receptor” for receptors acting at the interface between dietary components and signalling molecules.

Section snippets

Materials and methods

Materials. Fatty acids and fatty acid derivatives were from the following commercial suppliers: Larodan AB, Malmö, Sweden; Sigma and Cayman Chemical, Ann Arbor, MI. Rosiglitazone was a gift from GlaxoSmithKline. Coelentrazine was purchased from BioSynth AG. Cell culture reagents, equipment, and media were obtained from Invitrogen and oligonucleotides from MWG Biotech.

Cloning. Cloning of the R10/GPR40 ORF from human genomic DNA was performed by PCR using the following primers: forward: 5

Linoleic acid specifically activates receptor 10 (R10) expressing reporter cell lines

We used a highly sensitive reporter system [11] equipped with ten different putative human GPCRs for which the endogenous activating ligands are still unknown. The receptor sequences were selected from GenBank, based on a reasonably high sequence homology to the receptors for leukotriene B4 (an AA derivative), previously cloned in our laboratory [14], [15]. During the initial screening, reporter cell lines with or without individual recombinant test receptors were challenged with FFAs, such as

Acknowledgements

This work was supported by GS Development, the Segerfalk Foundation, Crafoord Foundation, Ingabritt and Arne Lundberg Foundation, Kock Foundation, Swedish Society for Medical Research, Royal Physiographic Society, and Swedish Research Council.

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    These authors contributed equally to this work.

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