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Free Fatty Acids Inhibit Insulin Signaling–Stimulated Endothelial Nitric Oxide Synthase Activation Through Upregulating PTEN or Inhibiting Akt Kinase
Ist Teil von
Diabetes (New York, N.Y.), 2006-08, Vol.55 (8), p.2301-2310
Ort / Verlag
Alexandria, VA: American Diabetes Association
Erscheinungsjahr
2006
Link zum Volltext
Quelle
EZB Electronic Journals Library
Beschreibungen/Notizen
Free Fatty Acids Inhibit Insulin Signaling–Stimulated Endothelial Nitric Oxide Synthase Activation Through Upregulating PTEN
or Inhibiting Akt Kinase
Xing Li Wang ,
Lin Zhang ,
Keith Youker ,
Ming-Xiang Zhang ,
Jian Wang ,
Scott A. LeMaire ,
Joseph S. Coselli and
Ying H. Shen
From the Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas
Address correspondence and reprint requests to Dr. Ying. H. Shen MS NAB 2010, Baylor College of Medicine, One Baylor Plaza,
Houston, TX 77030. E-mail: hyshen{at}bcm.edu ; or Dr. Xing Li Wang, MS NAB 2010, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. E-mail: xlwang{at}bcm.edu
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.
ATF, activating transcription factor
CREBP, cAMP-responsive element–binding protein
EBM, endothelial cell basic medium
eNOS, endothelial nitric oxide synthase
FFA, free fatty acid
HAEC, human aortic endothelial cell
JNK, Jun NH2-terminal kinase
PDK, phosphoinositide-dependent kinase
PI, phosphatidylinositol
PIP3, phosphatidylinositol-3.4,5-triphosphate
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted May 22, 2006.
Received December 5, 2005.
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