title: AICAR inhibits PPARγ during monocyte differentiation to attenuate inflammatory responses to atherogenic lipids.
abstract: OBJECTIVE
  Transcriptional regulation through peroxisome proliferator-activated receptor γ (PPARγ) is critical for an altered lipid metabolism during monocyte to macrophage differentiation. Here, we investigated how 5-aminoimidazole-4-carboxamide riboside (AICAR), an activator of AMP-dependent protein kinase (AMPK), affects PPARγ during monocyte differentiation.
  
  
  RESULTS
  During the differentiation of THP-1 monocytic cells or primary human monocytes to macrophages, we observed that AICAR inhibited the expression of PPARγ target genes, such as fatty acid-binding protein 4 or CD36. This effect was independent of AICAR conversion to AICAR ribotide and AMPK activation. While AICAR increased PPARγ mRNA expression that paralleled differentiation, it inhibited PPARγ protein synthesis without affecting PPARγ protein stability. Monocytes differentiated to macrophages in the presence of AICAR revealed an attenuated uptake of oxidized low-density lipoprotein (oxLDL) and reduced oxLDL-triggered c-Jun N-terminal kinase (JNK) activation. JNK and endoplasmic reticulum stress responses to the saturated fatty acid palmitate were attenuated as well, an effect mimicked by the knockdown of PPARγ. Although PPARγ has been reported to support alternative macrophage activation, AICAR did not inhibit interleukin-4-induced gene expression in differentiating monocytes.
  
  
  CONCLUSIONS
  Inhibition of PPARγ-dependent gene expression during monocyte differentiation may contribute to an AICAR-elicited macrophage phenotype characterized by reduced inflammatory responses to modified lipoproteins and saturated fatty acids.
authors.affiliation: Faculty of Medicine, Institute of Biochemistry I/ZAFES, Goethe-University Frankfurt, Theodor-Stern-Kai 7, Frankfurt 60590 Germany.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Namgaladze
authors.forename: Marina
authors.initials: M
authors.lastname: Kemmerer
authors.forename: Andreas
authors.initials: A
authors.lastname: von Knethen
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019308:Palmitic Acid / Q000378:metabolism; D010641:Phenotype; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology*; D014162:Transfection
chemical_list: D000893:Anti-Inflammatory Agents; D020536:Enzyme Activators; C508598:IL4 protein, human; D008077:Lipoproteins, LDL; D047495:PPAR gamma; D012333:RNA, Messenger; D012265:Ribonucleotides; C099252:oxidized low density lipoprotein; D015847:Interleukin-4; D019308:Palmitic Acid; D000620:Aminoimidazole Carboxamide; D048031:JNK Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide
keywords: Fatty acids; Lipoproteins; Macrophages; Metabolism; Oxidized lipids