PPARγ In Macrophages Research Articles

Differential Regulation of Macrophage Peroxisome Proliferator–Activated Receptor Expression by Glucose

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 PPARalpha and PPARbeta mRNA expression. In contrast, this treatment significantly decreased human macrophage PPARgamma mRNA expression. Overexpression of PPARalpha and PPARbeta mRNA and inhibition of PPARgamma mRNA expression were also observed in monocyte-derived macrophages isolated from patients with type 2 diabetes. Because high glucose and PPARalpha agonists increase lipoprotein lipase (LPL) gene expression, the role of PPARalpha 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 PPARalpha 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-PPARalpha and anti-PPARbeta 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 PPARalpha and PPARbeta 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.

Response to autologous immunoglobulin G in patients with rheumatoid arthritis.

Vitamin D has long been linked to resistance to tuberculosis, an infectious respiratory disease that is increasingly hard to treat because of multidrug resistance. Previous work established that vitamin D induces macrophage antimicrobial functions against <i>Mycobacterium tuberculosis</i>. In this article, we report a novel, metabolic role for vitamin D in tuberculosis identified through integrated transcriptome and mechanistic studies. Transcriptome analysis revealed an association between vitamin D receptor (VDR) and lipid metabolism in human tuberculosis and infected macrophages. Vitamin D treatment of infected macrophages abrogated infection-induced accumulation of lipid droplets, which are required for intracellular <i>M. tuberculosis</i> growth. Additional transcriptomics results showed that vitamin D downregulates the proadipogenic peroxisome proliferator–activated receptor γ (PPARγ) in infected macrophages. PPARγ agonists reversed the antiadipogenic and the antimicrobial effects of VDR, indicating a link between VDR and PPARγ signaling in regulating both vitamin D functions. These findings suggest the potential for host-based, adjunct antituberculosis therapy targeting lipid metabolism.