AMPK inhibits fatty acid-induced increases in NF-kappaB transactivation in cultured human umbilical vein endothelial cells.
The fuel sensing enzyme AMP-activated protein kinase (AMPK) enhances processes that generate ATP when stresses such as exercise or glucose deprivation make cells energy deficient. We report here a novel role of AMPK, to prevent the activation of NF-kappaB in endothelial cells exposed to the fatty acid palmitate or the cytokine TNF-alpha. Incubation of cultured human umbilical vein endothelial cells (HUVEC) with elevated levels of palmitate (0.4mM) increased NF-kappaB reporter gene expression by 2- to 4-fold within 8h and caused a 7-fold increase in VCAM-1 mRNA expression at 24h. In contrast, no increase in reporter gene expression was detected for AP-1, glucocorticoid-, cyclic AMP-, or serum response elements. Similar increases in NF-kappaB activation and VCAM-1 expression were not observed in cells incubated with an elevated concentration of glucose (25mM). The increases in NF-kappaB activation and VCAM-1 expression caused by palmitate were markedly inhibited by co-incubation with the AMPK activator AICAR and, where studied, by expression of a constitutively active AMPK. Likewise, AMPK activation inhibited the increase in NF-kappaB reporter gene expression observed in HUVEC incubated with TNF-alpha. The results suggest that AMPK inhibits the activation of NF-kappaB caused by both palmitate and TNF-alpha. The mechanism responsible for this action, as well as its relevance to the reported anti-atherogenic actions of exercise, metformin, thiazolidinediones, and adiponectin, all of which have been shown to activate AMPK, remains to be determined.
Cacicedo
Jose M
JM
Diabetes and Metabolism Research Unit, Department of Medicine and Section of Endocrinology, Boston University School of Medicine, 650 Albany St., 8th Floor, Room 820, Boston, MA 02118, USA.
Yagihashi
Norito
N
Keaney
John F
JF
Ruderman
Neil B
NB
Ido
Yasuo
Y
D055372:AMP-Activated Protein Kinases; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D009097:Multienzyme Complexes / Q000502:physiology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010168:Palmitates / Q000037:antagonists & inhibitors*; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014471:Umbilical Veins / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics
D009097:Multienzyme Complexes; D016328:NF-kappa B; D010168:Palmitates; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases