IUPHAR DATABASE | 0B. DAX-like receptors

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SHP

Systematic Nomenclature: NR0B2

Family: 0B. DAX-like receptors

Contents:

Gene and Protein Information

Previous and Unofficial Names

Physiological Consequences of Altering Gene Expression

Phenotypes, Alleles and Disease Models

Clinically-Relevant Mutations and Pathophysiology

General Comments

References

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

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
Ensembl	ENSG00000131910 (Hs), ENSMUSG00000037583 (Mm), ENSRNOG00000007229 (Rn)
Entrez Gene	8431 (Hs), 23957 (Mm), 117274 (Rn)
GeneCards	NR0B2 (Hs)
GenitoUrinary Development Molecular Anatomy Project	Nr0b2 (Mm)
Human Protein Reference Database	05219 (Hs)
InterPro	Q15466 (Hs), Q62227 (Mm), P97947 (Rn)
KEGG Gene	hsa:8431 (Hs), mmu:23957 (Mm), rno:117274 (Rn)
NURSA Receptor	0B2
PhosphoSitePlus	Q15466 (Hs), Q62227 (Mm), P97947 (Rn)
RefSeq Nucleotide	NM_021969 (Hs), NM_011850 (Mm), NM_057133 (Rn)
RefSeq Protein	NP_068804 (Hs), NP_035980 (Mm), NP_476474 (Rn)
TreeFam	ENSG00000131910 (Hs), ENSMUSG00000037583 (Mm), ENSRNOG00000007229 (Rn)
UniProt	Q15466 (Hs), Q62227 (Mm), P97947 (Rn)
Wikipedia	SHP
	Orphan nuclear receptors

Search for 3D structures on the PDB
Search by keyword: SHP	Search by accession number: Q15466, Q62227, P97947

Natural/Endogenous Ligand(s)
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 gland, spleen , pancreas, adrenal glands, liver

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

Click here to show/hide data

Allele	Composition & genetic background	Accession	Phenotype Id	Phenotype	Reference
Nr0b2^tm1Ddm	Nr0b2^tm1Ddm/Nr0b2^tm1Ddm involves: 129 * C57BL/6	MGI:1346344	MP:0005365	abnormal bile salt homeostasis	PMID: 12062085
Nr0b2^tm1Rus	Nr0b2^tm1Rus/Nr0b2^tm1Rus involves: 129P2/OlaHsd * C57BL/6	MGI:1346344	MP:0005365	abnormal bile salt homeostasis	PMID: 12062084
Nr0b2^tm1Ddm	Nr0b2^tm1Ddm/Nr0b2^tm1Ddm involves: 129 * C57BL/6	MGI:1346344	MP:0004774	abnormal bile salt level	PMID: 12062085
Nr0b2^tm1Rus	Nr0b2^tm1Rus/Nr0b2^tm1Rus involves: 129P2/OlaHsd * C57BL/6	MGI:1346344	MP:0004774	abnormal bile salt level	PMID: 12062084
Nr0b2^tm1Rus	Nr0b2^tm1Rus/Nr0b2^tm1Rus involves: 129P2/OlaHsd * C57BL/6	MGI:1346344	MP:0002118	abnormal lipid homeostasis	PMID: 12062084
Nr0b2^tm1Rus	Nr0b2^tm1Rus/Nr0b2^tm1Rus involves: 129P2/OlaHsd * C57BL/6	MGI:1346344	MP:0000609	abnormal liver physiology	PMID: 12062084
Nr0b2^tm1.1Auw	Nr0b2^tm1.1Auw/Nr0b2^tm1.1Auw involves: 129S2/SvPas * C57BL/6J	MGI:1346344	MP:0004884	abnormal testicular physiology	PMID: 17289919
Nr0b2^tm1Ddm	Nr0b2^tm1Ddm/Nr0b2^tm1Ddm involves: 129 * C57BL/6	MGI:1346344	MP:0005179	decreased circulating cholesterol level	PMID: 12062085
Nr0b2^tm1Mjev\|Tg(Alb-cre)21Mgn	Nr0b2^tm1Mjev/Nr0b2^tm1Mjev,Tg(Alb-cre)21Mgn/0 involves: 129S/SvEvBrd * C57BL/6 * DBA	MGI:1346344 MGI:2176226	MP:0005179	decreased circulating cholesterol level	PMID: 18820241
Nr0b2^tm1.1Mjev	Nr0b2^tm1.1Mjev/Nr0b2^tm1.1Mjev involves: 129S/SvEvBrd * 129S4/SvJae	MGI:1346344	MP:0005179	decreased circulating cholesterol level	PMID: 18820241
Nr0b2^tm1.1Mjev	Nr0b2^tm1.1Mjev/Nr0b2^tm1.1Mjev involves: 129S/SvEvBrd * 129S4/SvJae	MGI:1346344	MP:0000186	decreased circulating HDL cholesterol level	PMID: 18820241
Nr0b2^tm1Mjev\|Tg(Alb-cre)21Mgn	Nr0b2^tm1Mjev/Nr0b2^tm1Mjev,Tg(Alb-cre)21Mgn/0 involves: 129S/SvEvBrd * C57BL/6 * DBA	MGI:1346344 MGI:2176226	MP:0000183	decreased circulating LDL cholesterol level	PMID: 18820241
Nr0b2^tm1.1Mjev	Nr0b2^tm1.1Mjev/Nr0b2^tm1.1Mjev involves: 129S/SvEvBrd * 129S4/SvJae	MGI:1346344	MP:0000183	decreased circulating LDL cholesterol level	PMID: 18820241
Ldlr^tm1Her\|Nr0b2^tm1.1Mjev	Ldlr^tm1Her/Ldlr^tm1Her,Nr0b2^tm1.1Mjev/Nr0b2^tm1.1Mjev involves: 129S/SvEvBrd * 129S4/SvJae * 129S7/SvEvBrd * C57BL/6	MGI:1346344 MGI:96765	MP:0000183	decreased circulating LDL cholesterol level	PMID: 18820241
Nr0b2^tm1.1Mjev	Nr0b2^tm1.1Mjev/Nr0b2^tm1.1Mjev involves: 129S/SvEvBrd * 129S4/SvJae	MGI:1346344	MP:0005146	decreased circulating VLDL cholesterol level	PMID: 18820241
Nr0b2^tm1.1Auw	Nr0b2^tm1.1Auw/Nr0b2^tm1.1Auw involves: 129S2/SvPas * C57BL/6J	MGI:1346344	MP:0004852	decreased testis weight	PMID: 17289919
Nr0b2^tm1.1Auw	Nr0b2^tm1.1Auw/Nr0b2^tm1.1Auw involves: 129S2/SvPas * C57BL/6J	MGI:1346344	MP:0003378	early sexual maturation	PMID: 17289919
Nr0b2^tm1Ddm	Nr0b2^tm1Ddm/Nr0b2^tm1Ddm involves: 129 * C57BL/6	MGI:1346344	MP:0004789	increased bile salt level	PMID: 12062085
Nr0b2^tm1Rus	Nr0b2^tm1Rus/Nr0b2^tm1Rus involves: 129P2/OlaHsd * C57BL/6	MGI:1346344	MP:0002646	increased cholesterol absorption	PMID: 12062084
Nr0b2^tm1Rus	Nr0b2^tm1Rus/Nr0b2^tm1Rus involves: 129P2/OlaHsd * C57BL/6	MGI:1346344	MP:0002941	increased circulating alanine transaminase level	PMID: 12062084
Nr0b2^tm1Rus	Nr0b2^tm1Rus/Nr0b2^tm1Rus involves: 129P2/OlaHsd * C57BL/6	MGI:1346344	MP:0005343	increased circulating aspartate transaminase level	PMID: 12062084
Ldlr^tm1Her\|Nr0b2^tm1.1Mjev	Ldlr^tm1Her/Ldlr^tm1Her,Nr0b2^tm1.1Mjev/Nr0b2^tm1.1Mjev involves: 129S/SvEvBrd * 129S4/SvJae * 129S7/SvEvBrd * C57BL/6	MGI:1346344 MGI:96765	MP:0001556	increased circulating HDL cholesterol level	PMID: 18820241
Nr0b2^tm1.1Auw	Nr0b2^tm1.1Auw/Nr0b2^tm1.1Auw involves: 129S2/SvPas * C57BL/6J	MGI:1346344	MP:0002781	increased circulating testosterone level	PMID: 17289919
Nr0b2^tm1.1Auw	Nr0b2^tm1.1Auw/Nr0b2^tm1.1Auw involves: 129S2/SvPas * C57BL/6J	MGI:1346344	MP:0004928	increased epididymis weight	PMID: 17289919
Nr0b2^tm1Ddm	Nr0b2^tm1Ddm/Nr0b2^tm1Ddm involves: 129 * C57BL/6	MGI:1346344	MP:0009355	increased liver triglyceride level	PMID: 12062085
Nr0b2^tm1Ddm	Nr0b2^tm1Ddm/Nr0b2^tm1Ddm involves: 129 * C57BL/6	MGI:1346344	MP:0010180	increased susceptibility to weight loss	PMID: 12062085
Nr0b2^tm1Auw	Nr0b2^tm1Auw/Nr0b2^tm1Auw involves: 129S2/SvPas * C57BL/6J	MGI:1346344	MP:0002169	no abnormal phenotype detected	PMID: 17289919
Nr0b2^tm1.1Auw	Nr0b2^tm1.1Auw/Nr0b2^tm1.1Auw involves: 129S2/SvPas * C57BL/6J	MGI:1346344	MP:0001147	small testis	PMID: 17289919

Clinically-Relevant Mutations and Pathophysiology

Disease:	Obesity (in relation with MODY)
OMIM:	604630
Comments:	Nishigori et collaborators identified mutations in the NR0B2 gene that segregated with mild or moderate early-onset obesity in Japanese subjects. In a screening of 173 unrelated Japanese subjects with early-onset diabetes, they identified 5 mutations in the NR0B2 gene, including an arg34-to-ter (R34X) mutation, in 6 moderately obese subjects. All of the mutations were present in heterozygous state and were found on further study to segregate with mild obesity rather than with diabetes. The R34X nonsense mutation was found also in 6 of 101 unrelated nondiabetic subjects with early-onset obesity. They also found an ala195-to-ser (A195S) missense mutation in the NR0B2 gene in mildly obese Japanese subjects with early-onset diabetes. The authors showed that the mutation segregated with early-onset mild obesity rather than with diabete
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. Gastroenterology, 121 (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. Biochemistry, 44 (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. Cell, 6 (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. Cell, 2 (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. Cell, 6 (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. Acta, 1350 (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. Science, 272 (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. Cell, 2 (6): 721-31. [PMID:12062085]

To cite this database page, please use the following:

0B. DAX-like receptors: SHP. Last modified on 07/01/2013. Accessed on 20/06/2013. IUPHAR database (IUPHAR-DB), http://iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=636.