TABLE 2

SHP

Receptor nomenclature NR0B2
Receptor code 4.10.1:OR:0:B2
Other names
Molecular information Hs: 257aa, Q15466, chr. 1p361
Rn: 260aa, P97947, chr. 5q362
Mm: 260aa, Q62227, chr. 4 D31
DNA binding
   Structure
   HRE core sequence SHP seems to be unable to bind DNA
Partners LRH-1 (physical, functional): inhibition of LRH-1 mediated gene expression modulation3; FXR (physical, functional): inhibition of FXR mediated gene expression modulation4; CAR (physical, functional): inhibition of CAR mediated gene expression modulation1,5,6 ; HNF-4 (physical, functional): inhibition of HNF-4 mediated gene expression modulation7; LXRα and LXRβ (physical, functional): inhibition of LXR mediated gene expression modulation8
Agonists
Antagonists
Coactivators
Corepressors HDAC1, HDAC3, Sin3A, CREBBP, NCOR1, NCOR25,6,9–12
Biologically important isoforms
Tissue distribution Liver, heart, adrenal gland, spleen, pancreas {Mm} [Northern blot, in situ hybridization]1,13,14
Functional assays
Main target genes Repressed: CYP7A1 {Hs, Mm, Rn},4,15 NTCP {Hs, Mm, Rn},16 ABCA1 {Hs, Mm, Rn},8 ACOX1 {Hs, Mm, Rn},17 PEPCK {Hs, Mm, Rn}18
Mutant phenotype SHP-null mice show gross accumulation and increased bile acid synthesis caused by derepression of the rate-limiting enzymes CYP7A1 and CYP8B1 {Mm} [disruption caused by insertion of a vector]19,20
Human disease Obesity (in relation with MODY): a recent study identified mutations in the NR0B2 gene that segregated with mild or moderate early onset obesity in Japanese subjects21

  • aa, amino acids; chr., chromosome; HRE, hormone response element; CREBBP, cAMP response element-binding protein binding protein; MODY, maturity onset of diabetes; NTCP, Na+/taurocholate-cotransporting protein; PEPCK, phosphoenolpyruvate carboxykinase

  • ↵1. Seol W, Choi HS, and Moore DD (1996) An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors. Science (Wash DC) 272: 1336-1339

  • ↵2. Masuda N, Yasumo H, Tamura T, Hashiguchi N, Furusawa T, Tsukamoto T, Sadano H, and Osumi T (1997) An orphan nuclear receptor lacking a zinc-finger DNA-binding domain: interaction with several nuclear receptors. Biochim Biophys Acta 1350: 27-32

  • ↵3. Lee YK and Moore DD (2002) Dual mechanisms for repression of the monomeric orphan receptor liver receptor homologous protein-1 by the orphan small heterodimer partner. J Biol Chem 277: 2463-2467

  • ↵4. Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB, Galardi C, Wilson JG, Lewis MC, Roth ME, et al. (2000) A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 6: 517-526

  • ↵5. Seol W, Chung M, and Moore DD (1997) Novel receptor interaction and repression domains in the orphan receptor SHP. Mol Cell Biol 17: 7126-7131

  • ↵6. Bae Y, Kemper JK, and Kemper B (2004) Repression of CAR-mediated transactivation of CYP2B genes by the orphan nuclear receptor, short heterodimer partner (SHP). DNA Cell Biol 23: 81-91

  • ↵7. Lee YK, Dell H, Dowhan DH, Hadzopoulou-Cladaras M, and Moore DD (2000) The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: two mechanisms for repression. Mol Cell Biol 20: 187-195

  • ↵8. Brendel C, Schoonjans K, Botrugno OA, Treuter E, and Auwerx J (2002) The small heterodimer partner interacts with the liver X receptor α and represses its transcriptional activity. Mol Endocrinol 16: 2065-2076

  • ↵9. Boulias K and Talianidis I (2004) Functional role of G9a-induced histone methylation in small heterodimer partner-mediated transcriptional repression. Nucleic Acids Res 32: 6096-6103

  • ↵10. Gobinet J, Carascossa S, Cavailles V, Vignon F, Nicolas JC, and Jalaguier S (2005) SHP represses transcriptional activity via recruitment of histone deacetylases. Biochemistry 44: 6312-6320

  • ↵11. Kemper JK, Kim H, Miao J, Bhalla S, and 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: 7707-7719

  • ↵12. Bavner A, Johansson L, Toresson G, Gustafsson JA, and Treuter E (2002) A transcriptional inhibitor targeted by the atypical orphan nuclear receptor SHP. EMBO Rep 3: 478-484

  • ↵13. Lee HK, Lee YK, Park SH, Kim YS, Lee JW, Kwon HB, Soh J, Moore DD, and Choi HS (1998) Structure and expression of the orphan nuclear receptor SHP gene. J Biol Chem 273: 14398-14402

  • ↵14. Lee YK, Parker KL, Choi HS, and Moore DD (1999) Activation of the promoter of the orphan receptor SHP by orphan receptors that bind DNA as monomers. J Biol Chem 274: 20869-20873

  • ↵15. Lu TT, Makishima M, Repa JJ, Schoonjans K, Kerr TA, Auwerx J, and Mangelsdorf DJ (2000) Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 6: 507-515

  • ↵16. Denson LA, Sturm E, Echevarria W, Zimmerman TL, Makishima M, Mangelsdorf DJ, and Karpen SJ (2001) The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp. Gastroenterology 121: 140-147

  • ↵17. Kassam A, Capone JP, and Rachubinski RA (2001) The short heterodimer partner receptor differentially modulates peroxisome proliferator-activated receptor α -mediated transcription from the peroxisome proliferator-response elements of the genes encoding the peroxisomal β -oxidation enzymes acyl-CoA oxidase and hydratase-dehydrogenase. Mol Cell Endocrinol 176: 49-56

  • ↵18. Borgius LJ, Steffensen KR, Gustafsson JA, and Treuter E (2002) Glucocorticoid signaling is perturbed by the atypical orphan receptor and corepressor SHP. J Biol Chem 277: 49761-49766

  • ↵19. Wang L, Lee YK, Bundman D, Han Y, Thevananther S, Kim CS, Chua SS, Wei R, Heyman RA, Karin M, et al. (2002) Redundant pathways for negative feedback regulation of bile acid production. Dev Cell 2: 721-731

  • ↵20. Kerr TA, Saeki S, Schneider M, Schaefer K, Berdy S, Redder T, Shan B, Russell DW, and Schwarz M (2002) Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis. Dev Cell 2: 713-720

  • ↵21. Nishigori H, Tomura H, Tonooka N, Kanamori M, Yamada S, Sho K, Inoue I, Kikuchi N, Onigata K, Kojima I, et al. (2001) Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects. Proc Natl Acad Sci USA 98: 575-580