INVITED REVIEW Dietary modification of metabolic pathways via nuclear hormone receptors Gianella Caiozzi, Brian S. Wong and Marie-Louise Ricketts* Department of Agriculture, Nutrition and Veterinary Sciences, University of Nevada Reno, Reno, Nevada, USA Nuclear hormone receptors (NHRs), as ligand-dependent transcription factors, have emerged as important mediators in th body metabolism. Because of the promiscuous nature of several members of this superfamily that have been found to bin affinity than the classical steroid NHRs, they consequently display a broader ligand selectivity. This promiscuous nature has facilitated various bioactive dietary components being able to act as agonist ligands for certain members of the NHR superfamily. By NHRs, bioactive dietary components are able to mediate changes in various metabolic pathways, including, glucose, cholesterol and triglyceride homeostasis among others. This review will provide a general overview of the nuclear hormone receptors tha to be activated by dietary components. The physiological consequences of such receptor activation by these dietary com discussed in more detail. Copyright © 2012 John Wiley & Sons, Ltd. key words—nuclear hormone receptors; cafestol; isoflavones; probiotics; GSPE; phytosterols INTRODUCTION Nuclear hormone receptors Nuclear hormone receptors (NHRs) are ligand dependent, and in some cases, ligand independent, transcription factors that mediate changes in gene expression via interaction with nuclear proteins that act as co-activators and co-repressors. 1 The human genome contains 48 members of this superfamily, whereasthemousegenomecontains49 members, 2–4 including receptors for steroid and thyroid hormones, retinoic acid, vitamin D,bile acids,oxysterols and fatty acids. NHRs are involved in key biological processes such as development, reproduction, cell growth,cell cycle progression, differentiation, apoptosis, immunity and me- tabolism, 5 making them necessary for all stagesof life from embryonic development to whole body metabolic homeostasis in the adult. Using molecular phylogeny based on sequence homology, the receptors have been classified into seven subfamilies; namely, NR1, NR2, NR3, NR4, NR5, NR6 and NR0. 6 The majority of the members of the NHR superfamily contain five domains: a DNA binding domain (DBD),which contains two zinc fingerDNA binding motifs, 7 and governs the direct interaction with NHR dimers and their corresponding response elements (which can either be located within the promoter region of their respective target genes, or for receptors such as e trogen, androgen, glucocorticoid receptors and peroxisom proliferator receptor g, receptor binding sites can be loca distally from thepromoter, in intergenicand intronic regions 8 ); a ligand binding domain (LBD), which forms a pocketfor direct interaction with specific endogenous, or pharmacological ligands; and two activation domains: one located in the amino terminus (AF-1), and one in the carboxy terminus (AF-2) (Figure 1). The AF-2 domain is involved in ligand binding as well as co-activator binding, whereas transcriptional activation of the AF-1 domain is independent of ligand, 9 and the AF-1 region tends to be highly variable in both length and sequence between various NH The N-terminal DBD targetsthe receptor to a response element; and coupled by a flexible hinge region to the LB the binding ofsmalllipophillichormones is facilitated, serving as a switch to initiate gene transcription. 3,10 Regula- tion of transcription by NHRs is a complex process that re on ligand-dependent recruitment of different co-regulatory proteins (co-activators) to a surface on the LBD that, in tu mediates interactions with the basal transcriptional mach resulting in repression or activation of transcription. 11 The binding of agonist ligand to the LBD induces a conforma- tionalchange in the receptor that releases bound transcrip- tional co-repressor proteins and creates a binding surface *Correspondence to: Marie-Louise Ricketts, Department of Agriculture, Nutrition and Veterinary Sciences, College of Agriculture, Biotechnology and Natural Resources, University of Nevada, Reno, 1664 N. Virginia St, MS 202, Reno, Nevada 89557, USA. E-mail: mricketts@cabnr.unr.edu Received 1 December 2011 Revised 7 April 2012 Accepted 9 May 2012 Copyright © 2012 John Wiley & Sons, Ltd. cell biochemistry and function Cell Biochem Funct (2012) Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/cbf.2842