Abstract
Nuclear hormone receptors are a family of transcription factors regulated by small molecules derived from the endogenous metabolism or diet. There are forty-eight nuclear hormone receptors in the human genome, twenty of which are still orphans. In this review, we make a brief historical journey from the first observations by Berthold in 1849 to the era of orphan receptors that began with the sequencing of the Caenorhabditis elegans genome in 1998. We discuss the evolution of nuclear hormone receptors and the putative ancestral ligands as well as how the ligand universe has expanded over time. This leads us to define four classes of metabolites—fatty acids, terpenoids, porphyrins and amino acid derivatives—that generate all known ligands for nuclear hormone receptors. We conclude by discussing the ongoing efforts to identify new classes of ligands for orphan receptors.
Highlights
As a family, nuclear hormone receptors (NHRs) represent some of the most biologically important transcription factors that integrate cellular metabolism and function
NHR activities are controlled by binding to small molecules or ligands derived from endogenous metabolism, hormones or vitamins obtained from the diet [1]
We focus on metabolic pathways that produce ligands for NHRs and the mechanisms by which NHR ligands mediate intercellular communication
Summary
Nuclear hormone receptors (NHRs) represent some of the most biologically important transcription factors that integrate cellular metabolism and function. NHR activities are controlled by binding to small molecules or ligands derived from endogenous metabolism, hormones or vitamins obtained from the diet [1]. The resulting conformational changes allow recruitment of co-activators and induction of target gene expression on promoters containing a positive hormone receptor element or target gene repression on promoters containing a negative hormone receptor element [3]. Metabolites are widely used for intercellular communication in both prokaryotes and eukaryotes [5]. We focus on metabolic pathways that produce ligands for NHRs and the mechanisms by which NHR ligands mediate intercellular communication
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