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Papers In Press, published online ahead of print June 21, 2004
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Department of Nutrition, University of Montreal, Montreal, Quebec H2L 4M1
Corresponding Author: genevieve.renier{at}umontreal.ca
Objective: Recent evidences indicate that lipoprotein lipase (LPL) secreted by macrophages in the arterial wall promotes atherosclerosis. We have previously shown that macrophages of patients with type 2 diabetes overproduce LPL and that metabolic factors dysregulated in diabetes, including glucose, stimulate macrophage LPL secretion in vitro. In the present study, we determined the effect of advanced glycation end-products (AGE) on LPL expression by macrophages cultured in a high glucose environment and the molecular mechanisms underlying this effect. Methods and Results: Our results demonstrate that AGE potentiate the stimulatory effect of high glucose on murine and human macrophage LPL gene expression and secretion. Induction of macrophage LPL mRNA levels by AGE was identical to that elicited by physiologically relevant modified albumin (GlyBSA) and was inhibited by immunoneutralization of the AGE receptor (RAGE) as well as by antioxidants. Treatment of macrophages with AGE resulted in protein kinase C (PKC) and mitogen-activated protein kinases (MAPK) activation. Inhibition of these kinases abolished the stimulatory effect of AGE on LPL mRNA levels. Finally, exposure of macrophages to AGE increased the binding of nuclear proteins to the activated protein-1 (AP-1) consensus sequence of the LPL promoter. This effect was inhibited by PKC and MAPK inhibitors. Conclusion: Overall, these results demonstrated for the first time, that AGE potentiate the stimulatory effect of high glucose on macrophage LPL expression. This effect appears to involve increased oxidative stress and PKC/MAPK activation. Further studies are required to evaluate the relevance of our in vitro findings to the accelerated atherosclerosis associated with human diabetes.
Revised on June 4, 2004
Accepted on June 9, 2004
Advanced glycation end-products potentiate the stimulatory effect of glucose on macrophage lipoprotein lipase expression: Involvement of protein kinase C and mitogen-activated protein kinase
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