title: Free fatty acids inhibit insulin signaling-stimulated endothelial nitric oxide synthase activation through upregulating PTEN or inhibiting Akt kinase.
abstract: In metabolic syndrome, a systemic deregulation of the insulin pathway leads to a combined deregulation of insulin-regulated metabolism and cardiovascular functions. Free fatty acids (FFAs), which are increased in metabolic syndrome, inhibit insulin signaling and induce metabolic insulin resistance. This study was designed to examine FFAs' effects on vascular insulin signaling and endothelial nitric oxide (NO) synthase (eNOS) activation in endothelial cells. We showed that FFAs inhibited insulin signaling and eNOS activation through different mechanisms. While linoleic acid inhibited Akt-mediated eNOS phosphorylation, palmitic acid appeared to affect the upstream signaling. Upregulation of PTEN (phosphatase and tensin homolog deleted on chromosome 10) activity and transcription by palmitic acid mediated the inhibitory effects on insulin signaling. We further found that activated stress signaling p38, but not Jun NH(2)-terminal kinase, was involved in PTEN upregulation. The p38 target transcriptional factor activating transcription factor (ATF)-2 bound to the PTEN promoter, which was increased by palmitic acid treatment. In summary, both palmitic acid and linoleic acid exert inhibitory effect on insulin signaling and eNOS activation in endothelial cells. Palmitic acid inhibits insulin signaling by promoting PTEN activity and its transcription through p38 and its downstream transcription factor ATF-2. Our findings suggest that FFA-mediated inhibition of vascular insulin signaling and eNOS activation may contribute to cardiovascular diseases in metabolic syndrome.
authors.affiliation: DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. xlwang@bcm.edu
authors.forename: Xing Li
authors.initials: XL
authors.lastname: Wang
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Keith
authors.initials: K
authors.lastname: Youker
authors.forename: Ming-Xiang
authors.initials: MX
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Scott A
authors.initials: SA
authors.lastname: LeMaire
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Coselli
authors.forename: Ying H
authors.initials: YH
authors.lastname: Shen
mesh_terms: D051698:Activating Transcription Factor 2 / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019787:Linoleic Acid / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000502:physiology; D019308:Palmitic Acid / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D019308:Palmitic Acid; D019787:Linoleic Acid; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human