title: AMP-Activated Protein Kinase Interacts with the Peroxisome Proliferator-Activated Receptor Delta to Induce Genes Affecting Fatty Acid Oxidation in Human Macrophages.
abstract: AMP-activated protein kinase (AMPK) maintains energy homeostasis by suppressing cellular ATP-consuming processes and activating catabolic, ATP-producing pathways such as fatty acid oxidation (FAO). The transcription factor peroxisome proliferator-activated receptor δ (PPARδ) also affects fatty acid metabolism, stimulating the expression of genes involved in FAO. To question the interplay of AMPK and PPARδ in human macrophages we transduced primary human macrophages with lentiviral particles encoding for the constitutively active AMPKα1 catalytic subunit, followed by microarray expression analysis after treatment with the PPARδ agonist GW501516. Microarray analysis showed that co-activation of AMPK and PPARδ increased expression of FAO genes, which were validated by quantitative PCR. Induction of these FAO-associated genes was also observed upon infecting macrophages with an adenovirus coding for AMPKγ1 regulatory subunit carrying an activating R70Q mutation. The pharmacological AMPK activator A-769662 increased expression of several FAO genes in a PPARδ- and AMPK-dependent manner. Although GW501516 significantly increased FAO and reduced the triglyceride amount in very low density lipoproteins (VLDL)-loaded foam cells, AMPK activation failed to potentiate this effect, suggesting that increased expression of fatty acid catabolic genes alone may be not sufficient to prevent macrophage lipid overload.
authors.affiliation: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Kemmerer
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Marburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Finkernagel
authors.affiliation: Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Marcela Frota
authors.initials: MF
authors.lastname: Cavalcante
authors.affiliation: Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Dulcineia Saes Parra
authors.initials: DS
authors.lastname: Abdalla
authors.affiliation: Institute of Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Marburg, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.affiliation: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
authors.affiliation: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Namgaladze
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism*; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000102:Acetyl-CoA C-Acyltransferase / Q000378:metabolism*; D000704:Analysis of Variance; D001713:Biphenyl Compounds; D015153:Blotting, Western; D019748:Carbon-Carbon Double Bond Isomerases / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004746:Enoyl-CoA Hydratase / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D046228:Microarray Analysis; D016297:Mutagenesis, Site-Directed; D010101:Oxygen Consumption; D047494:PPAR delta / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D011753:Pyrones / Q000494:pharmacology; D019998:Racemases and Epimerases / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D001713:Biphenyl Compounds; D017931:DNA Primers; C425931:GW 501516; D047494:PPAR delta; D011753:Pyrones; D013844:Thiazoles; D013876:Thiophenes; C038784:fatty acid oxidation complex; D015094:3-Hydroxyacyl CoA Dehydrogenases; D000102:Acetyl-CoA C-Acyltransferase; C526222:PRKAG1 protein, human; D055372:AMP-Activated Protein Kinases; D004746:Enoyl-CoA Hydratase; D019998:Racemases and Epimerases; D019748:Carbon-Carbon Double Bond Isomerases; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile