title: Saturated fatty acids regulate retinoic acid signalling and suppress tumorigenesis by targeting fatty acid-binding protein 5.
abstract: Long chain fatty acids (LCFA) serve as energy sources, components of cell membranes and precursors for signalling molecules. Here we show that these biological compounds also regulate gene expression and that they do so by controlling the transcriptional activities of the retinoic acid (RA)-activated nuclear receptors RAR and PPARβ/δ. The data indicate that these activities of LCFA are mediated by FABP5, which delivers ligands from the cytosol to nuclear PPARβ/δ. Both saturated and unsaturated LCFA (SLCFA, ULCFA) bind to FABP5, thereby displacing RA and diverting it to RAR. However, while SLCFA inhibit, ULCFA activate the FABP5/PPARβ/δ pathway. We show further that, by concomitantly promoting the activation of RAR and inhibiting the activation of PPARβ/δ, SLCFA suppress the oncogenic properties of FABP5-expressing carcinoma cells in cultured cells and in vivo. The observations suggest that compounds that inhibit FABP5 may constitute a new class of drugs for therapy of certain types of cancer.
authors.affiliation: Department of Cellular &Molecular Medicine, Cleveland Clinic, 9500 Euclid Avenue, NC-10, Cleveland, Ohio 44195, USA.
authors.forename: Liraz
authors.initials: L
authors.lastname: Levi
authors.affiliation: Department of Cellular &Molecular Medicine, Cleveland Clinic, 9500 Euclid Avenue, NC-10, Cleveland, Ohio 44195, USA.|Center for Cardiovascular Diagnostics &Prevention, Cleveland Clinic, 9500 Euclid Avenue, NC-10, Cleveland, Ohio 44195, USA.
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Cellular &Molecular Medicine, Cleveland Clinic, 9500 Euclid Avenue, NC-10, Cleveland, Ohio 44195, USA.|Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Mary Kathryn
authors.initials: MK
authors.lastname: Doud
authors.affiliation: Department of Cellular &Molecular Medicine, Cleveland Clinic, 9500 Euclid Avenue, NC-10, Cleveland, Ohio 44195, USA.|Center for Cardiovascular Diagnostics &Prevention, Cleveland Clinic, 9500 Euclid Avenue, NC-10, Cleveland, Ohio 44195, USA.|Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, NC-10, Cleveland, Ohio 44195, USA.
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.affiliation: Department of Cellular &Molecular Medicine, Cleveland Clinic, 9500 Euclid Avenue, NC-10, Cleveland, Ohio 44195, USA.|Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Noa
authors.initials: N
authors.lastname: Noy
mesh_terms: D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism; D048068:PPAR-beta / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014212:Tretinoin / Q000378:metabolism*
chemical_list: C493412:FABP5 protein, human; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D047494:PPAR delta; D048068:PPAR-beta; D018168:Receptors, Retinoic Acid; D014212:Tretinoin