Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors

Abstract

Biological systems are integrated networks constantly responding to internal and external stimulators. Understanding the intrinsic response to an imbalanced system provides the opportunity to develop therapeutic approaches to reinstate the natural balanced state. Increasing evidence suggests that members of the nuclear receptor superfamily integrate both inflammatory and metabolic signals to maintain homeostasis in immune cells such as macrophages and lymphocytes. PPAR and LXR are nuclear receptors activated by fatty acid and cholesterol derivatives respectively that control the expression of an array of genes involved in lipid metabolism and inflammation. Recent studies have uncovered distinct mechanisms for transcriptional regulation of metabolic and inflammatory target genes by PPAR and LXR and have expanded the biology of these receptors to include roles in alternative macrophage activation and adaptive immunity.

Figure 1

Regulation of cholesterol and inflammatory signaling by LXR. Uptake of oxidized LDL by macrophages leads to increased intracellular levels of cholesterol and oxysterols and to LXR activation. LXR induces expression of cholesterol efflux transporters ABCA1 and ABCG1 through direct promoter activation. LXR activation also blunts the expression of inflammatory gene expression triggered by stimuli such as TLR ligands and cytokines. Inhibition of inflammation by LXR occurs via the mechanism of transrepression.

Figure 2

A role for PPAR signaling in alternative (M2) macrophage activation. Recentr studies suggest that cytokines such as IL-4 and IL-13 promote alternative macrophage activation through a pathway that requires PPARγ and PPARδ transcriptional activity. PPARs directly regulate expression of the M2 marker Arg I and promote mitochondrial biogenesis and oxidative metabolism to support the M2 phenotype. The balance between less inflammatory M2 cells and classically activated M1 macrophages is altered in mice lacking PPARs and has been proposed be involved in the pathogenesis of insulin resistance.