Nuclear receptors, transcription factors linking lipid metabolism and immunity: the case of peroxisome proliferator-activated receptor gamma.

ABSTRACT

Exposure to lipids has a major effect on mammalian cells. Naturally, it has a profound impact on their metabolism, but it can also significantly alter their cellular and molecular phenotypes and responses. This latter is via specific signalling pathways leading to alterations in the expression of genes and gene networks. Multicellular organisms utilize a specialized group of proteins to detect and transduce lipid signals to the level of the expression of the genome. These proteins, termed nuclear hormone receptors, are lipid-activated transcription factors regulating gene expression upon binding of small fatty ligands. In this review, we discuss the role and contribution of peroxisome proliferator-activated receptor gamma (PPAR gamma) to macrophage and dendritic cell biology and also to gut epithelial cell function. We discuss how using different experimental systems and approaches the pathways activating the receptor and its target genes can be identified and complex biological processes unravelled. It appears that PPAR gamma is part of the macrophage's response to pathogenic lipoproteins and it coordinately regulates lipid uptake and efflux. Intriguingly, in another cell type of the immune system, dendritic cells, the receptor has overlapping, but distinct functions. In these cells, activation of PPAR gamma leads to altered immune phenotype characterized by increased phagocytic capacity, antigen processing and lipid antigen presenting capacity. This nuclear hormone receptor links lipid metabolism and immune cell function and these links provide unique insights into the regulatory logic of normal physiological responses and certain pathologies, such as atherosclerosis, chronic inflammatory diseases and autoimmunity.