title: Increase of palmitic acid concentration impairs endothelial progenitor cell and bone marrow-derived progenitor cell bioavailability: role of the STAT5/PPARγ transcriptional complex.
abstract: Metabolic profiling of plasma nonesterified fatty acids discovered that palmitic acid (PA), a natural peroxisome proliferator-activated receptor γ (PPARγ) ligand, is a reliable type 2 diabetes biomarker. We investigated whether and how PA diabetic (d-PA) concentrations affected endothelial progenitor cell (EPC) and bone marrow-derived hematopoietic cell (BM-HC) biology. PA physiologic (n-PA) and d-PA concentrations were used. Proliferating cell nuclear antigen content and signal transducer and activator of transcription 5 (STAT5), PPARγ, cyclin D1, and p21(Waf) expression were evaluated. Small interfering RNA technology, gene reporter luciferase assay, electrophoretic mobility shift assay, chromatin immunoprecipitation assay, and coimmunoprecipitation were exploited. In vivo studies and migration assays were also performed. d-PA, unlike n-PA or physiological and diabetic oleic and stearic acid concentrations, impaired EPC migration and EPC/BM-HC proliferation through a PPARγ-mediated STAT5 transcription inhibition. This event did not prevent the formation of a STAT5/PPARγ transcriptional complex but was crucial for gene targeting, as p21(Waf) gene promoter, unlike cyclin D1, was the STAT5/PPARγ transcriptional target. Similar molecular events could be detected in EPCs isolated from type 2 diabetic patients. By expressing a constitutively activated STAT5 form, we demonstrated that STAT5 content is crucial for gene targeting and EPC fate. Finally, we also provide in vivo data that d-PA-mediated EPC dysfunction could be rescued by PPARγ blockade. These data provide first insights on how mechanistically d-PA drives EPC/BM-HC dysfunction in diabetes.
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Trombetta
authors.forename: Gabriele
authors.initials: G
authors.lastname: Togliatto
authors.forename: Arturo
authors.initials: A
authors.lastname: Rosso
authors.forename: Patrizia
authors.initials: P
authors.lastname: Dentelli
authors.forename: Cristina
authors.initials: C
authors.lastname: Olgasi
authors.forename: Paolo
authors.initials: P
authors.lastname: Cotogni
authors.forename: Maria Felice
authors.initials: MF
authors.lastname: Brizzi
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000145:classification* / Q000166:cytology / Q000187:drug effects; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000145:classification* / Q000166:cytology / Q000187:drug effects; D005786:Gene Expression Regulation / Q000502:physiology; D006410:Hematopoiesis / Q000502:physiology; D006801:Humans; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D019308:Palmitic Acid / Q000097:blood / Q000378:metabolism* / Q000633:toxicity; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000145:classification* / Q000166:cytology / Q000187:drug effects
chemical_list: D047495:PPAR gamma; D050799:STAT5 Transcription Factor; D019308:Palmitic Acid