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Journal of Lipid Research, Vol. 45, 1749-1757, September 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Advanced glycation end products potentiate the stimulatory effect of glucose on macrophage lipoprotein lipase expression

Marie-Claude Beauchamp, Sophie-Élise Michaud, Ling Li, Maryam Radimeh Sartippour and Geneviève Renier¹

Centre Hospitalier de l'Université de Montréal Research Centre, Notre-Dame Hospital, Department of Nutrition, University of Montreal, Montreal, Quebec, Canada

¹ To whom correspondence should be addressed. e-mail: genevieve.renier{at}umontreal.ca

Lipoprotein lipase (LPL) secreted by macrophages in the arterial wall promotes atherosclerosis. We have shown that macrophages of patients with type 2 diabetes overproduce LPL and that metabolic factors, including glucose, stimulate macrophage LPL secretion. In this study, we determined the effect of advanced glycation end products (AGEs) on LPL expression by macrophages cultured in a high-glucose environment and the molecular mechanisms underlying this effect. Our results demonstrate that AGEs potentiate the stimulatory effect of high glucose on murine and human macrophage LPL gene expression and secretion. Induction of macrophage LPL mRNA levels by AGEs was identical to that elicited by physiologically relevant modified albumin and was inhibited by anti-AGE receptor as well as by antioxidants. Treatment of macrophages with AGEs resulted in protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) activation. Inhibition of these kinases abolished the effect of AGEs on LPL mRNA levels. Finally, exposure of macrophages to AGEs increased the binding of nuclear proteins to the activated protein-1 consensus sequence of the LPL promoter. This effect was inhibited by PKC and MAPK inhibitors.

These results demonstrate for the first time that AGEs potentiate the stimulatory effect of high glucose on macrophage LPL expression. This effect appears to involve oxidative stress and PKC/MAPK activation.

Supplementary key words oxidative stress • kinases • diabetes • atherosclerosis

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