An integrated biological approach to nuclear receptor signaling in physiological control and disease.
The nuclear receptors (NRs)--vitamin D receptor (VDR); peroxisome proliferator-activated receptor (PPAR) alpha, delta, gamma; and pregnane X receptor (PXR)--act as sensors for various molecules encountered by the body on a daily basis. The effects of these ligands can be understood by the fact that numerous genes involved in the cellular processes, such as general homeostasis, growth, and defense against microbes, are under the control of these five NRs. The target gene and protein expression patterns of VDR, PPARs, and PXR; the resulting changes in metabolite levels; and their physiological consequences create a network that can be monitored by high-throughput methods and analyzed by multimodal approaches, such as systems biology. We suggest that the fine regulation of this NR network is specific to each human individual and depends, in part, on the constellation of regulatory small nucleotide polymorphisms (SNPs) in his or her genome. When regulatory SNPs affect NRs response elements, lifetime exposure to food components will have different accumulative consequences on the expression of the respective NR target genes. These differences will influence the individual's susceptibility to aging-related diseases, such as type 2 diabetes, atherosclerosis, cancer, and osteoporosis. Furthermore, it is anticipated that systems biology methods will also help to identify the most critical genes, proteins, or metabolites in the NR network that will serve as biomarkers for the early detection of these diseases.
Carlberg
Carsten
C
Department of Biochemistry, University of Kuopio, FIN-70211 Kuopio, Finland. carlberg@messi.uku.fi
Dunlop
Thomas W
TW
D019295:Computational Biology; D005786:Gene Expression Regulation / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D023281:Genomics; D006801:Humans; D009747:Nutritional Physiological Phenomena; D020641:Polymorphism, Single Nucleotide; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction / Q000235:genetics
D018160:Receptors, Cytoplasmic and Nuclear