SHP

Nomenclature: SHP

Systematic Nomenclature: NR0B2

Family: 0B. DAX-like receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

Gene and Protein Information
Species AA Chromosomal Location Gene Symbol Gene Name Reference
Human 257 1p36 NR0B2 nuclear receptor subfamily 0, group B, member 2 18
Mouse 260 4 60.0 cM Nr0b2 nuclear receptor subfamily 0, group B, member 2 18
Rat 260 5q36 Nr0b2 nuclear receptor subfamily 0, group B, member 2 16
Previous and Unofficial Names
Small heterodimer partner
nuclear receptor subfamily 0 group B member 2
nuclear receptor subfamily 0, group B, member 2
orphan nuclear receptor SHP
small heterodimer partner homologue
SHP-1
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
Human Protein Reference Database
InterPro
KEGG Gene
NURSA Receptor
OMIM
PhosphoSitePlus
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniProtKB
Wikipedia
Natural/Endogenous Ligands
Comments: Orphan
Main Co-regulators
Name Activity Specific Ligand dependent AF-2 dependent Comments References
SIN3A Co-repressor - No - 1,11
HDAC3 Co-repressor No No No 8
HDAC1 Co-repressor - No - 1,3,8
EID1 Co-repressor Yes No - 5
NCOR1 Co-repressor - No - 1
NCOR2 Co-repressor - No - 1,19
Main Co-regulators Comments
SHP mediates part of its repressive effect through recruitment of HDACs, suggesting that the physiological actions of SHP could be affected by HDAC inhibitors. Evidence indicates that SHP interacts with the Sin3A-Swi/Snf complex by direct interaction with Brm and mSin3A through its repression domain.
Main Target Genes
Name Species Effect Technique Comments References
CYP7A1 Human Repressed Transient transfection SHP represses expression of CYP7A1 by inhibiting the activity of liver receptor homolog 1 (LRH-1), an orphan nuclear receptor that is known to regulate CYP7A1 expression positively. 9,15
SLC10A1 Human Repressed Transient transfection, others Solute carrier family 10 member 1(SLC10A1, or NTCP) is the principal hepatic bile acid transporter. SHP inhbits NTCP expression via direct interaction and inhibition of the RAR:RXR heterodimers. 7
ABCA1 Human Repressed Transient transfection, others SHP represses the expression of the ABCA1 gene which encodes the ATP-binding cassette transporter 1 via its interaction with the LXRalpha and beta, known transcriptional activator of ABCA1. 4
ACOX1 Human Repressed Transient transfection, others SHP differentially inhibits peroxisome proliferator-activated receptor alpha-mediated transcription from the peroxisome proliferator-response elements of the genes encoding the peroxisomal beta-oxidation enzymes acyl-CoA oxidase 10
PCK1 Human Repressed Transient transfection, others SHP inhibits GR mediated transactivation of the PCK1 (PEPCK) promoter by competing with GR coactivators and by perturbing GR intranuclear localization. 2
Main Target Genes Comments
All the target genes mentioned are also repressed likewise in all other species tested.
Tissue Distribution
Liver, heart, adrenal glands, spleen, pancreas
Species:  Mouse
Technique:  Northern, in situ, other
References:  13-14,18
Tissue Distribution Comments
SHP is encoded by a 1.3 kb transcript expressed in liver and at lower levels in heart, adrenal gland, spleen and pancreas. It has been shown that the SHP promoter is activated by SF-1 (NR5A1) and its paralogue LRH1 (NR5A2). The mouse SHP promoter was shown to contains 5 SFREs that are all required for the activation by NR5A subfamily members. In addition, it was shown that SHP is coexpressed with SF1 in adrenal glands as well as with LRH1 in liver.
Physiological Consequences of Altering Gene Expression
SHP null mice show gross accumulation and increased bile acids synthesis caused by derepression of the rate-limiting enzymes CYP7A1 and CYP8B1
Species:  Mouse
Tissue: 
Technique:  Knock out (disruption caused by insertion of vector)
References:  12,20
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Nr0b2tm1Ddm Nr0b2tm1Ddm/Nr0b2tm1Ddm
involves: 129 * C57BL/6
MGI:1346344  MP:0005365 abnormal bile salt homeostasis PMID: 12062085 
Nr0b2tm1Rus Nr0b2tm1Rus/Nr0b2tm1Rus
involves: 129P2/OlaHsd * C57BL/6
MGI:1346344  MP:0005365 abnormal bile salt homeostasis PMID: 12062084 
Nr0b2tm1Ddm Nr0b2tm1Ddm/Nr0b2tm1Ddm
involves: 129 * C57BL/6
MGI:1346344  MP:0004774 abnormal bile salt level PMID: 12062085 
Nr0b2tm1Rus Nr0b2tm1Rus/Nr0b2tm1Rus
involves: 129P2/OlaHsd * C57BL/6
MGI:1346344  MP:0004774 abnormal bile salt level PMID: 12062084 
Nr0b2tm1Rus Nr0b2tm1Rus/Nr0b2tm1Rus
involves: 129P2/OlaHsd * C57BL/6
MGI:1346344  MP:0002118 abnormal lipid homeostasis PMID: 12062084 
Nr0b2tm1Rus Nr0b2tm1Rus/Nr0b2tm1Rus
involves: 129P2/OlaHsd * C57BL/6
MGI:1346344  MP:0000609 abnormal liver physiology PMID: 12062084 
Nr0b2tm1.1Auw Nr0b2tm1.1Auw/Nr0b2tm1.1Auw
involves: 129S2/SvPas * C57BL/6J
MGI:1346344  MP:0004884 abnormal testicular physiology PMID: 17289919 
Nr0b2tm1Ddm Nr0b2tm1Ddm/Nr0b2tm1Ddm
involves: 129 * C57BL/6
MGI:1346344  MP:0005179 decreased circulating cholesterol level PMID: 12062085 
Nr0b2tm1Mjev|Tg(Alb-cre)21Mgn Nr0b2tm1Mjev/Nr0b2tm1Mjev,Tg(Alb-cre)21Mgn/0
involves: 129S/SvEvBrd * C57BL/6 * DBA
MGI:1346344  MGI:2176226  MP:0005179 decreased circulating cholesterol level PMID: 18820241 
Nr0b2tm1.1Mjev Nr0b2tm1.1Mjev/Nr0b2tm1.1Mjev
involves: 129S/SvEvBrd * 129S4/SvJae
MGI:1346344  MP:0005179 decreased circulating cholesterol level PMID: 18820241 
Nr0b2tm1.1Mjev Nr0b2tm1.1Mjev/Nr0b2tm1.1Mjev
involves: 129S/SvEvBrd * 129S4/SvJae
MGI:1346344  MP:0000186 decreased circulating HDL cholesterol level PMID: 18820241 
Nr0b2tm1Mjev|Tg(Alb-cre)21Mgn Nr0b2tm1Mjev/Nr0b2tm1Mjev,Tg(Alb-cre)21Mgn/0
involves: 129S/SvEvBrd * C57BL/6 * DBA
MGI:1346344  MGI:2176226  MP:0000183 decreased circulating LDL cholesterol level PMID: 18820241 
Nr0b2tm1.1Mjev Nr0b2tm1.1Mjev/Nr0b2tm1.1Mjev
involves: 129S/SvEvBrd * 129S4/SvJae
MGI:1346344  MP:0000183 decreased circulating LDL cholesterol level PMID: 18820241 
Ldlrtm1Her|Nr0b2tm1.1Mjev Ldlrtm1Her/Ldlrtm1Her,Nr0b2tm1.1Mjev/Nr0b2tm1.1Mjev
involves: 129S/SvEvBrd * 129S4/SvJae * 129S7/SvEvBrd * C57BL/6
MGI:1346344  MGI:96765  MP:0000183 decreased circulating LDL cholesterol level PMID: 18820241 
Nr0b2tm1.1Mjev Nr0b2tm1.1Mjev/Nr0b2tm1.1Mjev
involves: 129S/SvEvBrd * 129S4/SvJae
MGI:1346344  MP:0005146 decreased circulating VLDL cholesterol level PMID: 18820241 
Nr0b2tm1.1Auw Nr0b2tm1.1Auw/Nr0b2tm1.1Auw
involves: 129S2/SvPas * C57BL/6J
MGI:1346344  MP:0004852 decreased testis weight PMID: 17289919 
Nr0b2tm1.1Auw Nr0b2tm1.1Auw/Nr0b2tm1.1Auw
involves: 129S2/SvPas * C57BL/6J
MGI:1346344  MP:0003378 early sexual maturation PMID: 17289919 
Nr0b2tm1Ddm Nr0b2tm1Ddm/Nr0b2tm1Ddm
involves: 129 * C57BL/6
MGI:1346344  MP:0004789 increased bile salt level PMID: 12062085 
Nr0b2tm1Rus Nr0b2tm1Rus/Nr0b2tm1Rus
involves: 129P2/OlaHsd * C57BL/6
MGI:1346344  MP:0002646 increased cholesterol absorption PMID: 12062084 
Nr0b2tm1Rus Nr0b2tm1Rus/Nr0b2tm1Rus
involves: 129P2/OlaHsd * C57BL/6
MGI:1346344  MP:0002941 increased circulating alanine transaminase level PMID: 12062084 
Nr0b2tm1Rus Nr0b2tm1Rus/Nr0b2tm1Rus
involves: 129P2/OlaHsd * C57BL/6
MGI:1346344  MP:0005343 increased circulating aspartate transaminase level PMID: 12062084 
Ldlrtm1Her|Nr0b2tm1.1Mjev Ldlrtm1Her/Ldlrtm1Her,Nr0b2tm1.1Mjev/Nr0b2tm1.1Mjev
involves: 129S/SvEvBrd * 129S4/SvJae * 129S7/SvEvBrd * C57BL/6
MGI:1346344  MGI:96765  MP:0001556 increased circulating HDL cholesterol level PMID: 18820241 
Nr0b2tm1.1Auw Nr0b2tm1.1Auw/Nr0b2tm1.1Auw
involves: 129S2/SvPas * C57BL/6J
MGI:1346344  MP:0002781 increased circulating testosterone level PMID: 17289919 
Nr0b2tm1.1Auw Nr0b2tm1.1Auw/Nr0b2tm1.1Auw
involves: 129S2/SvPas * C57BL/6J
MGI:1346344  MP:0004928 increased epididymis weight PMID: 17289919 
Nr0b2tm1Ddm Nr0b2tm1Ddm/Nr0b2tm1Ddm
involves: 129 * C57BL/6
MGI:1346344  MP:0009355 increased liver triglyceride level PMID: 12062085 
Nr0b2tm1Ddm Nr0b2tm1Ddm/Nr0b2tm1Ddm
involves: 129 * C57BL/6
MGI:1346344  MP:0010180 increased susceptibility to weight loss PMID: 12062085 
Nr0b2tm1Auw Nr0b2tm1Auw/Nr0b2tm1Auw
involves: 129S2/SvPas * C57BL/6J
MGI:1346344  MP:0002169 no abnormal phenotype detected PMID: 17289919 
Nr0b2tm1.1Auw Nr0b2tm1.1Auw/Nr0b2tm1.1Auw
involves: 129S2/SvPas * C57BL/6J
MGI:1346344  MP:0001147 small testis PMID: 17289919 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Obesity, mild, early-onset
OMIM:  601665
Comments: 
References:  17
Mutations not determined
General Comments
For a complete review on SHP see [6].

References

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1. Bae Y, Kemper JK, Kemper B. (2004) Repression of CAR-mediated transactivation of CYP2B genes by the orphan nuclear receptor, short heterodimer partner (SHP). DNA Cell Biol.23 (2): 81-91. [PMID:15000748]

2. Borgius LJ, Steffensen KR, Gustafsson JA, Treuter E. (2002) Glucocorticoid signaling is perturbed by the atypical orphan receptor and corepressor SHP. J. Biol. Chem.277 (51): 49761-6. [PMID:12324453]

3. Boulias K, Talianidis I. (2004) Functional role of G9a-induced histone methylation in small heterodimer partner-mediated transcriptional repression. Nucleic Acids Res.32 (20): 6096-103. [PMID:15550569]

4. Brendel C, Schoonjans K, Botrugno OA, Treuter E, Auwerx J. (2002) The small heterodimer partner interacts with the liver X receptor alpha and represses its transcriptional activity. Mol. Endocrinol.16 (9): 2065-76. [PMID:12198243]

5. Båvner A, Johansson L, Toresson G, Gustafsson JA, Treuter E. (2002) A transcriptional inhibitor targeted by the atypical orphan nuclear receptor SHP. EMBO Rep.3 (5): 478-84. [PMID:11964378]

6. Båvner A, Sanyal S, Gustafsson JA, Treuter E. (2005) Transcriptional corepression by SHP: molecular mechanisms and physiological consequences. Trends Endocrinol. Metab.16 (10): 478-88. [PMID:16275121]

7. Denson LA, Sturm E, Echevarria W, Zimmerman TL, Makishima M, Mangelsdorf DJ, Karpen SJ. (2001) The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp. Gastroenterology121 (1): 140-7. [PMID:11438503]

8. Gobinet J, Carascossa S, Cavaillès V, Vignon F, Nicolas JC, Jalaguier S. (2005) SHP represses transcriptional activity via recruitment of histone deacetylases. Biochemistry44 (16): 6312-20. [PMID:15835920]

9. Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB, Galardi C, Wilson JG, Lewis MC, Roth ME, Maloney PR, Willson TM, Kliewer SA. (2000) A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol. Cell6 (3): 517-26. [PMID:11030332]

10. Kassam A, Capone JP, Rachubinski RA. (2001) The short heterodimer partner receptor differentially modulates peroxisome proliferator-activated receptor alpha-mediated transcription from the peroxisome proliferator-response elements of the genes encoding the peroxisomal beta-oxidation enzymes acyl-CoA oxidase and hydratase-dehydrogenase. Mol. Cell. Endocrinol.176 (1-2): 49-56. [PMID:11369442]

11. Kemper JK, Kim H, Miao J, Bhalla S, Bae Y. (2004) Role of an mSin3A-Swi/Snf chromatin remodeling complex in the feedback repression of bile acid biosynthesis by SHP. Mol. Cell. Biol.24 (17): 7707-19. [PMID:15314177]

12. Kerr TA, Saeki S, Schneider M, Schaefer K, Berdy S, Redder T, Shan B, Russell DW, Schwarz M. (2002) Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis. Dev. Cell2 (6): 713-20. [PMID:12062084]

13. Lee HK, Lee YK, Park SH, Kim YS, Park SH, Lee JW, Kwon HB, Soh J, Moore DD, Choi HS. (1998) Structure and expression of the orphan nuclear receptor SHP gene. J. Biol. Chem.273 (23): 14398-402. [PMID:9603951]

14. Lee YK, Parker KL, Choi HS, Moore DD. (1999) Activation of the promoter of the orphan receptor SHP by orphan receptors that bind DNA as monomers. J. Biol. Chem.274 (30): 20869-73. [PMID:10409629]

15. Lu TT, Makishima M, Repa JJ, Schoonjans K, Kerr TA, Auwerx J, Mangelsdorf DJ. (2000) Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol. Cell6 (3): 507-15. [PMID:11030331]

16. Masuda N, Yasumo H, Tamura T, Hashiguchi N, Furusawa T, Tsukamoto T, Sadano H, Osumi T. (1997) An orphan nuclear receptor lacking a zinc-finger DNA-binding domain: interaction with several nuclear receptors. Biochim. Biophys. Acta1350 (1): 27-32. [PMID:9003453]

17. Nishigori H, Tomura H, Tonooka N, Kanamori M, Yamada S, Sho K, Inoue I, Kikuchi N, Onigata K, Kojima I, Kohama T, Yamagata K, Yang Q, Matsuzawa Y, Miki T, Seino S, Kim MY, Choi HS, Lee YK, Moore DD, Takeda J. (2001) Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects. Proc. Natl. Acad. Sci. U.S.A.98 (2): 575-80. [PMID:11136233]

18. Seol W, Choi HS, Moore DD. (1996) An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors. Science272 (5266): 1336-9. [PMID:8650544]

19. Seol W, Chung M, Moore DD. (1997) Novel receptor interaction and repression domains in the orphan receptor SHP. Mol. Cell. Biol.17 (12): 7126-31. [PMID:9372944]

20. Wang L, Lee YK, Bundman D, Han Y, Thevananther S, Kim CS, Chua SS, Wei P, Heyman RA, Karin M, Moore DD. (2002) Redundant pathways for negative feedback regulation of bile acid production. Dev. Cell2 (6): 721-31. [PMID:12062085]

How to cite this page

0B. DAX-like receptors: SHP. Last modified on 25/03/2014. Accessed on 23/09/2014. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=636.