Molecular Basis of Endocrine Regulation by Orphan Nuclear Receptor Small Heterodimer Partner

Abstract

Abstract. Nuclear receptors (NRs) are a unique superfamily of transcription factors (TFs) which are involved in and play a crucial role in almost all aspects of mammalian physiology. Small Heterodimer Partner (SHP; NR0B2), an exceptional member of this superfamily of NRs, have been identified as a key regulatory factor of the transcription of a variety of genes involved in diverse metabolic pathways, and are thereby an important factor in a variety of physiological functions. Since its discovery a decade ago, considerable progress has been made in the elucidation of the underlying mechanism by which SHP regulates various metabolic processes, and the results of previous studies support its importance in the maintenance of metabolic homeostasis. In this review, we have evaluated the current state of understanding of the molecular mechanisms and the resultant physiological interpretations governed by SHP. SMALL Heterodimer Partner is a unique member of the mammalian nuclear receptor superfamily, which is clearly distinct from the conventional nuclear receptors, both structurally and functionally. It is classified into the "orphan" subfamily, due to the absence of any known ligand for this receptor, and appears to function as a transcriptional co-regulator of numerous nuclear receptors and transcription factors. The dosage-sensitive sex reversal-adrenal hypoplasia congenital region gene on the X chromosome, gene-1 (DAX-1; NR0B1) is the closest relative to SHP. Both belong to the same subfamily, and both share considerable functional and structural similarities with SHP. SHP owes its place in the nuclear receptor family to the presence of a putative ligand binding domain (LBD), although it lacks the classical DNA binding domain (DBD) which is generally detected among other nuclear receptors. Intensive research conducted following its discovery last decade has resulted in a clearer understanding of the molecular basis for the inhibitory functions of SHP on a variety of metabolic processes, thereby providing us with ample evidence regarding its importance as a key regulator in a number of signaling pathways [1,2]. Hub-based topological analysis of the nuclear receptor network has demonstrated the extensive connections existing among these receptors as the result of their similarity in terms of interaction and tissue expression, as well as a considerable number of feedback loops that work in concert in this network, with SHP playing a principal role as the hub protein within this network [3]. In this review, we have attempted to survey the entirety of the information available thus far concerning the structural and functional aspects of the orphan nuclear receptor SHP, hoping to acquire a detailed understanding of the physiological significance of the activity of SHP.

Arginine Methylation by PRMT5 at a Naturally Occurring Mutation Site Is Critical for Liver Metabolic Regulation by Small Heterodimer Partner

“…Hepatic expression of SHP WT led to decreased expression of the bile acid biosynthetic Cyp7a1 and Cyp8b1 genes, the lipogeneic Fas and Srebp-1c genes, and the bile acid transporter Bsep and Ntcp genes (Fig. 7D), as previously reported (1,3). Exogenous expression of SHP WT decreased expression of the gluconeogenic Pepck and G-6-pase genes, but the effects were not statistically significant.…”

“…FGF15/19 signaling is activated in response to elevated bile acid levels in the enterohepatic system in vivo (14), so it Furthermore, it will be interesting to determine whether decreased methylation of SHP is associated with metabolic disease, which is analogous to our recent findings that acetylation of FXR is normally dynamically regulated by p300 acetylase and SIRT1 deacetylase but highly elevated in metabolic disease states (17,18). SHP plays an important role in controlling lipid and glucose levels by inhibiting metabolic target genes in the liver and other metabolic tissues and is also involved in cell proliferation, apoptosis, and reproduction (1,3,11,35,36,39). Given that SHP plays important roles in such diverse mammalian physiology, PTMs may provide a mechanism for selective regulation of genes in biological processes.…”

“…SHP forms nonfunctional heterodimers with DNA binding transcriptional factors, including nuclear receptors, and thereby acts as a transcriptional corepressor in diverse biological processes, including metabolism, cell proliferation, apoptosis, and sexual maturation (1,3,11,35,36,39). Well-studied hepatic functions of SHP are the inhibition of bile acid biosynthesis, fatty acid synthesis, and glucose production in response to bile acid signaling (1,3,4,12,19,22,37,38). We previously showed that SHP inhibits the expression of a key bile acid biosynthetic gene, the CYP7A1 (cholesterol 7␣ hydroxylase) gene, by coordinately recruiting chromatin-modifying repressive cofactors, mSin3A/histone deacetylase 1 (HDAC1), NCoR/ HDAC3, methyltransferase G9a, and the Swi/Snf-Brm remodeling complex, to the CYP7A1 gene promoter (9,16,25).…”

Feedback regulation of hepatic gluconeogenesis through modulation of SHP/Nr0b2 gene expression by Sirt1 and FoxO1

“…In addition to regulation through the Sirt1-FXR pathway (20), the Sirt1-FoxO1 pathway also plays an important role in the regulation of the Nr0b2 gene expression. As an orphan nuclear receptor, Nr0b2 has been shown to inhibit numerous nuclear receptors and transcription factors, including HNF-4␣, CREB, and FoxO1 (4,5,23,33,47). Inactivation of hepatic Sirt1 not only attenuates the functions of PGC-1␣ and FoxO1 due to their hyperacetylation but may also dampen Nr0b2-mediated negative feedback on transcriptional activities of HNF-4␣, CREB, and FoxO1 due to decreased gene expression of Nr0b2.…”

AMPK-dependent Repression of Hepatic Gluconeogenesis via Disruption of CREB·CRTC2 Complex by Orphan Nuclear Receptor Small Heterodimer Partner

“…Orphan nuclear receptor SHP (NR0B2) lacks a typical nuclear receptor DNA-binding domain and is expressed predominantly in the liver, whereas nominal expression is also detected in the heart, lung, pancreas, spleen, kidney, smooth muscle, testis, and ovary (15,16). SHP is a transcriptional repressor of a number of nuclear receptors and transcription factors, including estrogen receptor (ER) (17,18), ER-related receptor (19), glucocorticoid receptor (20), androgen receptor (21), forkhead transcription factor FoxA2 (HNF3) (22), HNF4 (hepatocyte nuclear factor 4) (23), HNF6 (hepatocyte nuclear factor 6) (24), CCAAT/enhancer-binding protein ␣ (25), and BETA2/NeuroD (26).…”