AMP-Activated Protein Kinase Interacts with the Peroxisome Proliferator-Activated Receptor Delta to Induce Genes Affecting Fatty Acid Oxidation in Human Macrophages

• Published in: PloS one 2015-06, Vol.10 (6), p.e0130893
• Main Authors: Kemmerer, Marina, Finkernagel, Florian, Cavalcante, Marcela Frota, Abdalla, Dulcineia Saes Parra, Müller, Rolf, Brüne, Bernhard, Namgaladze, Dmitry
• Format: Article
• Language: English
• Subjects: 3-Hydroxyacyl CoA Dehydrogenases - metabolism; Acetyl-CoA C-Acyltransferase - metabolism; Adenoviruses; AMP; AMP-activated protein kinase; AMP-Activated Protein Kinases - metabolism; Analysis of Variance; ATP; Biochemistry; Blotting, Western; Carbon-Carbon Double Bond Isomerases - metabolism; Catalysis; Diabetes; DNA microarrays; DNA Primers - genetics; Endoplasmic reticulum; Energy balance; Enoyl-CoA Hydratase - metabolism; Fatty acids; Foam; Foams; Gene expression; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Genes; Glucose; Homeostasis; Humans; Inflammation; Insulin resistance; Kinases; Lipids; Lipoproteins; Lipoproteins (low density); Lipoproteins (very low density); Low density lipoprotein; Low density lipoproteins; Macrophages; Macrophages - metabolism; Metabolism; Microarray Analysis; Molecular biology; Musculoskeletal system; Mutagenesis, Site-Directed; Mutation; Obesity; Oxidation; Oxidation-reduction reactions; Oxygen Consumption; Penicillin; Pharmaceutical sciences; Pharmacology; Phosphorylation; Plasmids - genetics; PPAR delta - metabolism; Protein kinases; Proteins; Pyrones - pharmacology; Racemases and Epimerases - metabolism; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Thiazoles - pharmacology; Thiophenes - pharmacology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0130893

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.