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Metab Syndr Relat Disord. 2015 Mar;13(2):71-7. doi: 10.1089/met.2014.0101. Epub 2014 Dec 9.

Effect of hyperketonemia (Acetoacetate) on nuclear factor-κB and p38 mitogen-activated protein kinase activation mediated intercellular adhesion molecule 1 upregulation in endothelial cells.

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Department of Pediatrics and Department of Biochemistry and Molecular Biology Louisiana State University Health Sciences Center , Shreveport, Louisiana.



Hyperketonemia is a pathological condition observed in patients with type 1 diabetes and ketosis-prone diabetes (KPD), which results in increased blood levels of acetoacetate (AA) and β-hydroxybutyrate (BHB). Frequent episodes of hyperketonemia are associated with a higher incidence of vascular disease. We examined the hypothesis that hyperketonemia activates the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways that regulate intercellular adhesion molecule 1 (ICAM-1) expression in endothelial cells.


Human umbilical vein endothelial cells (HUVECs) were cultured with AA (0-8 mM) or BHB (0-10 mM) for 0-24 hr. Western blotting was used to determine NF-κB activation in whole-cell lysates. ICAM-1 expression was measured using flow cytometry.


RESULTS show a 2.4-fold increase in NF-κB activation in cells treated with 8 mM AA compared to the control. BHB had little or no effect on NF-κB activation. Pretreatment with a reactive oxygen species (ROS) inhibitor [N-acetyl-l-cysteine (NAC)] reduced NF-κB to near-control levels. The expression of AA-induced ICAM-1 was significantly reduced when cells were pretreated with either NAC or p38 MAPK inhibitor.


These results suggest that NF-κB and p38 MAPK mediate upregulation of ICAM-1 expression in endothelial cells exposed to elevated levels of AA, which may contribute to the development of vascular disease in diabetes.

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