Structure and Function of the Atypical Orphan Nuclear Receptor Small Heterodimer Partner

Lee, Yong-Soo; Chanda, Dipanjan; Sim, Jeonggu; Park, Yun‐Yong; Choi, Hueng-Sik

doi:10.1016/s0074-7696(07)61003-1

Cited by 63 publications

(73 citation statements)

References 107 publications

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“…The small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that functions as a co-repressor of transcription factors, including HNF-3␤, HNF-4␣, and FoxO1 (22). SHP plays a critical role in the maintenance of metabolic homeostasis, such as glucose, lipid, and bile acid metabolism (23).…”

Section: Growth Hormone (Gh)mentioning

confidence: 99%

Orphan Nuclear Receptor Small Heterodimer Partner Negatively Regulates Growth Hormone-mediated Induction of Hepatic Gluconeogenesis through Inhibition of Signal Transducer and Activator of Transcription 5 (STAT5) Transactivation

Kim

Ahn

et al. 2012

Journal of Biological Chemistry

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Background: Growth hormone (GH) is involved in hepatic glucose metabolism. Results: GH increased hepatic gluconeogenesis through STAT5 transactivation, which was abolished by the metformin-ATM-AMPK-SHP pathway. Conclusion:The metformin-ATM-AMPK-SHP network prevents the increase of hepatic gluconeogenesis by the GH-dependent pathway. Significance: The ATM-AMPK-SHP pathway may provide a novel mechanism for regulating hepatic glucose homeostasis via a GH-dependent pathway.

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Section: Growth Hormone (Gh)mentioning

confidence: 99%

Orphan Nuclear Receptor Small Heterodimer Partner Negatively Regulates Growth Hormone-mediated Induction of Hepatic Gluconeogenesis through Inhibition of Signal Transducer and Activator of Transcription 5 (STAT5) Transactivation

Kim

Ahn

et al. 2012

Journal of Biological Chemistry

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“…SHP has broad regulatory function by interaction with many nuclear factors. Animal experiments showed that SHP is an important target gene of FXR in the regulation of lipid metabolism [18].…”

Section: Introductionmentioning

confidence: 99%

Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease

2010

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Objective The aim of this study was to explore the role of farnesoid X receptor (FXR) in liver lipid metabolism of non-alcoholic fatty liver disease (NAFLD) patients. Methods In this study, pathology and clinical criteria confirmed NAFLD in patients. Fatty acid synthetase (FAS)-positive liver cells were visualized by laser scanning confocal microscopy. Levels of FXR, liver X receptor (LXR), sterol regulatory element binding protein 1C (SREBP-1C), and small heterodimer partner (SHP) proteins were detected by Western blot. FXR, LXR, and SHP mRNA levels were measured by real-time PCR. Results In patients with NAFLD, a significant positive relationship between the degree of hepatic steatosis and serum triglycerides and cholesterol (correlation coefficient [ 0.5, P \ 0.05) was seen. The NAFLD patients had more FAS protein in liver, which suggests that there could have been more of fatty acid synthesis in hepatic cells (P \ 0.05). The levels of FXR protein and mRNA were decreased in patients with NAFLD (P \ 0.05), while those of LXR and SREBP-1C were increased (P \ 0.05). The levels of SREBP-1C positively correlated with the degree of hepatic steatosis. There were no differences between the levels of SHP protein and mRNA both in NAFLD patients and normal controls (P [ 0.05).Conclusion Our data showed that the decreased expression of hepatic FXR is associated with an increased expression of LXR, SREBP-1C, and hepatic triglyceride synthesis; furthermore, increased SREBP-1C is associated with the degree of hepatic steatosis in the NAFLD patients.

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“…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].…”

mentioning

confidence: 99%

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

2008

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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.

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Structure and Function of the Atypical Orphan Nuclear Receptor Small Heterodimer Partner

Cited by 63 publications

References 107 publications

Orphan Nuclear Receptor Small Heterodimer Partner Negatively Regulates Growth Hormone-mediated Induction of Hepatic Gluconeogenesis through Inhibition of Signal Transducer and Activator of Transcription 5 (STAT5) Transactivation

Orphan Nuclear Receptor Small Heterodimer Partner Negatively Regulates Growth Hormone-mediated Induction of Hepatic Gluconeogenesis through Inhibition of Signal Transducer and Activator of Transcription 5 (STAT5) Transactivation

Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease

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

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