Dietary Phenolic Compounds Exert Some of Their Health-Promoting Bioactivities by Targeting Liver X Receptor (LXR) and Retinoid X Receptor (RXR)

Abstract

Consuming foods of vegetable origin has been shown to exert multiple health-related effects, many of them attributed to their phenolic compounds. These molecules are known for being bioactive across multiple cells and organs, with documented changes in gene expression being commonly reported. Nuclear receptors are signal transducers capable of regulating gene expression in response to endogenous and/or exogenous ligands. Liver X receptor (LXR) and retinoid X receptor (RXR) are two important nuclear receptors that can be acted on by phenolic compounds, thereby modifying gene expression and potentially exerting numerous subsequent bioactivities. The present work summarizes recent evidence of the effects of the phenolic compounds that are exerted by targeting LXR and/or RXR. The data show that, when LXR is being targeted, changes in lipid metabolism are commonly observed, due to its ability to regulate genes relevant to this process. The effects vary widely when RXR is the target since it is involved in processes like cell proliferation, vitamin D metabolism, and multiple others by forming heterodimers with other transcription factors that regulate said processes. The evidence therefore shows that phenolic compounds can exert multiple bioactivities, with a mechanism of action based, at least in part, on their ability to modulate the cell at the molecular level by acting on nuclear receptors. The data point to a promising and novel area of study that links diet and health, although various unknowns justify further experimentation to reveal the precise way in which a given phenolic can interact with a nuclear receptor.

Keywords: diet; fruits and vegetables; gene expression; mRNA expression; nuclear receptors.

Figure 1

Overall process of LXR and RXR activation. An appropriate extra- or intracellular ligand (1, yellow circle), oxysterols for LXR (represented in green) or 9-cis-retinoic acid for RXR (represented in blue), will bind to its corresponding receptor (2, 3) and form an active LXR/RXR heterodimer (4), while also weakening interactions with repressors (not shown). It is also possible for RXR to dimerize with itself or with other nuclear receptors (5) and form additional potential homo- or heterodimers (6). The active LXR/RXR heterodimer can bind to the consensus sequence 5′-AGGTCA-3′ (7), which results in activation of the transcription complex (8, dashed figures) and changes in the mRNA expression pattern of the cell (9). The transcripts are translated (10) into effector proteins (11) that can then exert specific health effects (12), such as normalization of cholesterol/lipid metabolism or inflammatory processes.

Figure 2

Overview of the metabolic processes modulated by RXR (center, represented in blue) and other nuclear receptors (represented in a different color for each one) with which it dimerizes. RXR can interact and dimerize with other nuclear receptors; clockwise from top-center, the LXR/RXR heterodimer mainly regulates cholesterol/lipid metabolism and inflammation. Thus, it has been widely associated with maintaining or normalizing serum cholesterol and the lipid profile overall. RXR can also dimerize with itself and modulate basic developmental and differentiation processes. The PPAR/RXR heterodimer regulates overall energy metabolism, as well as cellular differentiation. The PXR/RXR heterodimer responds to xenobiotic compounds, leading to the transcription of the genes necessary to prevent their accumulation and potential cell damage. The TR/RXR heterodimer responds to thyroid hormones, thereby participating in basal processes across most cells. The RAR/RXR heterodimer responds to retinoic acid isomers (9-cis or all-trans) and is associated with various basal metabolic, proliferation, and homeostatic processes. The FXR/RXR heterodimer responds to bile acids, and promotes the transcription of genes associated with their metabolism. Finally, the VDR/RXR heterodimer responds to vitamin D₃ (calcitriol), the active form of this vitamin, thereby participating in maintaining calcium and other mineral homeostasis. Because of the multiple processes under the direct or indirect control of RXR, changes in its activity by dietary phenolic compounds can result in numerous bioactivities across multiple cells and organs.