PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation

Abstract

Cells are constantly exposed to a large variety of lipids. Traditionally, these molecules were thought to serve as simple energy storing molecules. More recently it has been realized that they can also initiate and regulate signaling events that will decisively influence development, cellular differentiation, metabolism and related functions through the regulation of gene expression. Multicellular organisms dedicate a large family of nuclear receptors to these tasks. These proteins combine the defining features of both transcription factors and receptor molecules, and therefore have the unique ability of being able to bind lipid signaling molecules and transduce the appropriate signals derived from lipid environment to the level of gene expression. Intriguingly, the members of a subfamily of the nuclear receptors, the peroxisome proliferator-activated receptors (PPARs) are able to sense and interpret fatty acid signals derived from dietary lipids, pathogenic lipoproteins or essential fatty acid metabolites. Not surprisingly, Peroxisome proliferator-activated receptors were found to be key regulators of lipid and carbohydrate metabolism. Unexpectedly, later studies revealed that Peroxisome proliferator-activated receptors are also able to modulate inflammatory responses. Here we summarize our understanding on how these transcription factors/receptors connect lipid metabolism to inflammation and some of the novel regulatory mechanisms by which they contribute to homeostasis and certain pathological conditions. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.

Fig. 1

Number of publications on the role of PPARs in different types of inflammation. PubMed search was carried out with the combinations of the names of PPAR subtypes and certain inflammatory conditions. The total area of the pie diagrams correlates with the number of publications found (without reviews). Total number of publications (in parentheses) and percentage distribution of the three PPAR subtypes are indicated. The size of the sectors indicates the number of publications on distinct subtypes in inflammatory conditions.

Fig. 2

Mechanisms of genetic regulation by PPARs. (A) Upon ligand binding, PPARs induce gene expression. A subset of the induction, shown here, is the result of the direct regulation of gene expression by transactivation. Liganded PPAR/RXR heterodimers recruit co-activator molecules to promoters that contain PPAR response elements and subsequently activate gene expression. (B) A subset of direct target genes might be repressed by PPARs in the presence of ligands. However, the majority of characterized PPAR-mediated transcriptional regulations result in activation. (C) Ligand dependent trans-repression by PPARs. Upon ligand binding, PPARs can interfere with the activity of distinct transcription factors, such as NF-κB, through protein–protein interactions. (D) Ligand independent transrepression. Unliganded PPARs can bind and sequester transcription factors blocking their activity. A typical example for such a mechanism is the binding of BCL-6 by unliganded PPARβ/δ. (E) PPARs alter systemic lipid homeostasis which can affect gene regulation through unrelated transcription factors.