PPARγ and retinol binding protein 7 form a regulatory hub promoting antioxidant properties of the endothelium

Abstract

Peroxisome proliferator-activated receptors (PPARs) are a family of conserved ligand-activated nuclear receptor transcription factors heterogeneously expressed in mammalian tissues. PPARγ is recognized as a master regulator of adipogenesis, fatty acid metabolism, and glucose homeostasis, but genetic evidence also supports the concept that PPARγ regulates the cardiovascular system, particularly vascular function and blood pressure. There is now compelling evidence that the beneficial blood pressure-lowering effects of PPARγ activation are due to its activity in vascular smooth muscle and endothelium, through its modulation of nitric oxide-dependent vasomotor function. Endothelial PPARγ regulates the production and bioavailability of nitric oxide, while PPARγ in the smooth muscle regulates the vasomotor response to nitric oxide. We recently identified retinol binding protein 7 (RBP7) as a PPARγ target gene that is specifically and selectively expressed in the endothelium. In this review, we will discuss the evidence that RBP7 is required to mediate the antioxidant effects of PPARγ and mediate PPARγ target gene selectivity in the endothelium.

Keywords: PPAR; nuclear receptor; transcription.

Fig. 1.

Model illustrating the PPARγ-RBP7-adiponectin transcriptional hub. PPARγ is a nuclear transcription factor that induces expression of RBP7, an endothelial-specific PPARγ target gene. RBP7 facilitates transcriptional activation of RBP7-dependent PPARγ target genes including adiponectin. Expression of these genes is impaired in the absence of RBP7. Expression of adiponectin mediated an antioxidant response when the mice are challenged with either high-fat diet or angiotensin II. Impairment of this protective response under conditions where either RBP7 or PPARγ is impaired causes oxidative stress and endothelial dysfunction in the presence of cardiovascular stressors. PPARγ, peroxisome proliferator-activated receptor-γ; RBP7, retinol binding protein 7; HFD, high-fat diet; ANG II, angiotensin II. The figure and legend are reproduced with permission (23).

Fig. 2.

Model illustrating RBP7 nuclear translocation and PPARγ or RXR interaction. PPARγ is a nuclear transcription factor that exists as heterodimer with RXR bound to PPARγ response elements in chromatin. Under basal conditions, the PPARγ:RXR heterodimer is complexed with a co-repressor complex that is dismissed in the presence of ligand. We propose that based on homology and known function of other FABP/RBP, RBP7 is a ligand carrier protein localized in the cytoplasm. Expression of RBP7 is required for transcriptional activation of RBP7-dependent PPARγ target genes (23). Ligand binding to RBP7 induces a conformational change in RBP7 that unmasks a nuclear localization signal that drives its translocation into the nucleus. The spectrum of PPARγ or RXR ligands that bind to RBP7 remains unclear. Once in the nucleus, RBP7 facilitates ligand delivery to the PPARγ:RXR complex and subsequent transcriptional activity. The interaction between RBP7 and the PPARγ:RXR complex may be transient, as RBP7 channels the ligand to the complex and then is shuttled out of the nucleus. However, it is possible that in addition to ligand delivery, RBP7 may function as a coactivator of the PPARγ:RXR complex, resulting in the unique RBP7-dependent PPARγ target gene transcription pattern.