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.

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

“…Studies have identified many ligands that activate and modulate PPAR functions (Berger et al, 1999;Forman et al, 1995;Itoh et al, 2008;Kliewer et al, 1997;Sanderson et al, 2009;Varga et al, 2011). These ligands are summarized in Table 1.…”

“…The endogenous ligands for PPARα are dietary fatty acids, implying that diet can influence the immune system by activating PPARα-mediated gene expression (Varga et al, 2011). PPARα may suppress autoimmune diseases by regulating Th2 cytokine production.…”

“…PPARβ/δ -/-naïve CD4 + T cells are more prone to Th17 differentiation and hyper-responsive to TCR stimulation, as evidenced by the increased proliferation observed in these cells. Interestingly, PPARβ/δ has been hypothesized to bind the transcription factor B cell lymphoma 6 A B C (BCL6) and repress inflammation-related gene expression Takata et al, 2008;Varga et al, 2011).…”

“…The role of PPARs in lipid metabolism and inflammatory disease was elucidated by studying the effects of their respective ligands on gene expression (Varga et al, 2011). Similar to other nuclear receptors, PPARs have a conserved structure that includes an N-terminal ligand-independent activation domain, a highly conserved DNAbinding domain, a C-terminal ligand-binding domain, and a Cterminal ligand-dependent activation domain ( Fig.…”

Mammalian phospholipid homeostasis: Homeoviscous adaptation deconstructed by lipidomic data driven modelling

“…At the transcriptional level, membrane free fatty acids are implicated in the mechanisms of phospholipid homeostasis. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that act as transcription factors, sensing fatty acids and lipid metabolites (Varga et al, 2011). Similarly the sterol-regulatory element binding proteins (SREBPs) activate the expression of around 30 genes involved in the synthesis and uptake of fatty acids, cholesterol and phospholipids (Georgiadi and Kersten, 2012).…”