Differential regulation of macrophage peroxisome proliferator-activated receptor expression by glucose - Role of peroxisome proliferator-activated receptors in lipoprotein lipase gene expression

Peroxisome proliferator-activated receptors (PPARs) are implicated in several metabolic disorders with altered glucose and lipid metabolism, including atherosclerosis and diabetes. In the present study, we evaluated the in vitro and ex vivo effects of high glucose concentrations on macrophage PPAR mRNA expression. Exposition of monocyte-derived macrophages isolated from healthy donors to a high glucose environment led to an increase in PPAR alpha and PPAR beta mRNA expression. In contrast, this treatment significantly decreased human macrophage PPAR gamma mRNA expression. Overexpression of PPAR alpha and PPAR beta mRNA and inhibition of PPAR gamma mRNA expression were also observed in monocyte-derived macrophages isolated from patients with type 2 diabetes. Because high glucose and PPAR alpha agonists increase lipoprotein lipase (LPL) gene expression, the role of PPAR alpha in the glucose-mediated upregulation of macrophage LPL gene expression was next evaluated. Incubation of murine J774 macrophages with high glucose concentrations increased the expression of PPAR alpha at the mRNA and protein levels and enhanced nuclear protein binding to the peroxisome proliferator responsive element of the LPL promoter. Incubation of nuclear extracts in the presence of anti-PPAR alpha and anti-PPAR beta antibodies decreased glucose-stimulated nuclear protein binding to the peroxisome proliferator responsive element. These results demonstrate that glucose is an important regulator of macrophage PPAR expression and suggest a role of PPAR alpha and PPAR beta in the upregulation of macrophage LPL by glucose. Dysregulation of macrophage PPAR expression in type 2 diabetes may contribute, by altering arterial lipid metabolism and inflammatory response, to the accelerated atherosclerosis associated with diabetes.