Advanced glycation end products potentiate the stimulatory effect of glucose on macrophage lipoprotein lipase expression.
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.
Beauchamp
Marie-Claude
MC
Centre Hospitalier de l'Université de Montréal Research Centre, Notre-Dame Hospital, Department of Nutrition, University of Montreal, Montreal, Quebec, Canada.
Michaud
Sophie-Elise
SE
Li
Ling
L
Sartippour
Maryam Radimeh
MR
Renier
Geneviève
G
D000818:Animals; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006801:Humans; D008071:Lipoprotein Lipase / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism
D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D018808:Transcription Factor AP-1; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D008071:Lipoprotein Lipase; D005947:Glucose