Nuclear receptors: decoding metabolic disease - PubMed (original) (raw)

Review

Nuclear receptors: decoding metabolic disease

Junichiro Sonoda et al. FEBS Lett. 2008.

Abstract

Nuclear receptors (NR) are a superfamily of ligand-activated transcription factors that regulate development, reproduction, and metabolism of lipids, drugs and energy. The importance of this family of proteins in metabolic disease is exemplified by NR ligands used in the clinic or under exploratory development for the treatment of diabetes mellitus, dyslipidemia, hypercholesterolemia, or other metabolic abnormalities. Genetic studies in humans and rodents support the notion that NRs control a wide variety of metabolic processes by regulating the expression of genes encoding key enzymes, transporters and other proteins involved in metabolic homeostasis. Current knowledge of complex NR metabolic networks is summarized here.

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Figures

Figure 1

(A) Schematic diagrams for a common domain structure of NRs which include N-terminal activation function 1 (AF-1), DNA binding domain (DBD) consisting of two zinc fingers (ZF), nonconserved hinge-region (Hinge), ligand binding domain (LBD), and C-terminal AF-2 helix. (B) Schematic diagrams for NR dimerization and DNA binding sequences. From the left, homodimeric endocrine receptor (Palindrome HRE), RXR heterodimers (Direct Repeat HRE) and monomeric orphan receptor (Half Site HRE). Arrows: the consensus NR recognition sequence AGGTCA or a variant.

Figure 2

Schematic diagram for a typical NR activation mechanism. Top: In the absence of ligand, NRs form a repressive complex with HDACs (histone deacetylases) via corepressor SMRT or NCOR (left). Ligand binding induces a dissociation of corepressors and a recruitment of coactivators including HAT (histone acetyl-transferase) and chromatin remodeling complexes (right). Bottom: some nuclear receptors are activated by ligand-independendent binding of the PGC-1 coactivator and subsequent recruitment of additional coactivator complexes.

Figure 3

Human NR superfamily including 48 family members. Representative natural ligands are shown at right. Physiological importance of ligand-induced NR activation has been established for “Endocrine Receptors” (Pink: homodimerizing steroid receptors, and Green: RXR heterodimers) and “Adopted Orphan Receptors” (Orange), whereas it is not known for “Enigmatic Adopted Orphans” (Blue) and “Orphan receptors” (Grey). See text for details.

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Nuclear receptors: decoding metabolic disease - PubMed (original) (raw)