Abstract
Work over the past 30 years has shown that lipid-activated nuclear receptors form a bridge between metabolism and immunity integrating metabolic and inflammatory signaling in innate immune cells. Ligand-induced direct transcriptional activation and protein-protein interaction-based transrepression were identified as the most common mechanisms of liganded-nuclear receptor-mediated transcriptional regulation. However, the integration of different next-generation sequencing-based methodologies including chromatin immunoprecipitation followed by sequencing and global run-on sequencing allowed to investigate the DNA binding and ligand responsiveness of nuclear receptors at the whole-genome level. Surprisingly, these studies have raised the notion that a major portion of lipid-sensing nuclear receptor cistromes are not necessarily responsive to ligand activation. Although the biological role of the ligand insensitive portion of nuclear receptor cistromes is largely unknown, recent findings indicate that they may play roles in the organization of chromatin structure, in the regulation of transcriptional memory, and the epigenomic modification of responsiveness to other microenvironmental signals in macrophages. In this review, we will provide an overview and discuss recent advances of our understanding of lipid-activated nuclear receptor-mediated non-classical or unorthodox actions in macrophages.
Highlights
A generally accepted paradigm in endocrinology has been over the last 30 years that if not the sole, but the main function of lipid-sensing nuclear receptors is to translate microenvironmental chemical cues into distinct biological effects through tight regulation of gene transcription
The transrepression mechanism is not fully validated yet and requires additional studies. These findings indicate that lipid sensing nuclear receptors can act as macrophage subtype-specific lineage determining transcription factors (LDTFs) (Figure 2B) and having a much broader impact on macrophage biology, including the inflammatory response than previously thought and raising the issue that these activities might not be all requiring ligand activation
Previously we and others have identified many lipid sensing nuclear receptor-activated pathways, our knowledge was limited to the regulation of macrophage metabolism and inflammation through ligand-induced direct transcriptional activation and transrepression
Summary
A generally accepted paradigm in endocrinology has been over the last 30 years that if not the sole, but the main function of lipid-sensing nuclear receptors is to translate microenvironmental chemical cues into distinct biological effects through tight regulation of gene transcription. These early studies suggested that cell-type and cellular state-specific nuclear receptor cistromes are tightly dependent on other LDTFs or SDTFs and lipid-sensing nuclear receptors may act in a nonclassical, ligand-independent way.
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