title: Phytanic acid and pristanic acid, branched-chain fatty acids associated with Refsum disease and other inherited peroxisomal disorders, mediate intracellular Ca2+ signaling through activation of free fatty acid receptor GPR40.
abstract: The accumulation of the two branched-chain fatty acids phytanic acid and pristanic acid is known to play an important role in several diseases with peroxisomal impairment, like Refsum disease, Zellweger syndrome and α-methylacyl-CoA racemase deficiency. Recent studies elucidated that the toxic activity of phytanic acid and pristanic acid is mediated by multiple mitochondrial dysfunctions, generation of reactive oxygen species and Ca2+ deregulation via the InsP3-Ca2+ signaling pathway in glial cells. However, the exact signaling mechanism through which both fatty acids mediate toxicity is still under debate. Here, we studied the ability of phytanic acid and pristanic acid to activate the free fatty acid receptor GPR40, a G-protein-coupled receptor, which was described to be involved in the Ca2+ signaling of fatty acids. We treated HEK 293 cells expressing the GPR40 receptor with phytanic acid or pristanic acid. This resulted in a significant increase in the intracellular Ca2+ level, similar to the effect seen after treatment with the synthetic GPR40 agonist GW9508. Furthermore, we demonstrate that the GPR40 activation might be due to an interaction of the carboxylate moiety of fatty acids with the receptor. Our findings indicate that the phytanic acid- and pristanic acid-mediated Ca2+ deregulation can involve the activation of GPR40. Therefore, we suppose that activation of GPR40 might be part of the signaling cascade of the toxicity of phytanic and pristanic acids.
authors.affiliation: Institut für Neurobiochemie, Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Leipziger Str. 44, D-39120 Magdeburg, Germany.
authors.forename: Nicol
authors.initials: N
authors.lastname: Kruska
authors.forename: Georg
authors.initials: G
authors.lastname: Reiser
mesh_terms: D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000502:physiology; D007424:Intracellular Fluid / Q000187:drug effects* / Q000502:physiology; D019787:Linoleic Acid / Q000737:chemistry / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D008744:Methylamines / Q000737:chemistry / Q000494:pharmacology; D010831:Phytanic Acid / Q000737:chemistry / Q000494:pharmacology*; D011422:Propionates / Q000737:chemistry / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism* / Q000502:physiology; D012035:Refsum Disease / Q000378:metabolism*
chemical_list: C473034:FFAR1 protein, human; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; C515630:GW9508; D008744:Methylamines; D011422:Propionates; D043562:Receptors, G-Protein-Coupled; D010831:Phytanic Acid; C002844:pristanic acid; D015544:Inositol 1,4,5-Trisphosphate; D019787:Linoleic Acid