Disease relevance of Nr0b2

• Mice lacking SHP show increased basal expression of PGC-1alpha, increased energy expenditure, and resistance to diet-induced obesity [1].
• These results suggest that strategies aimed at increasing FXR activity and the repressive effects of SHP should be explored to correct hypertriglyceridemia [2].
• A negative regulatory role of Shp-1 in hematopoiesis has been strongly implicated by the phenotype of motheaten mice with a mutation in the Shp-1 locus, which is characterized by leukocyte hypersensitivity, deregulated mast cell function, and excessive erythropoiesis [3].
• These results identify an unexpected role for SHP in hepatotoxicity and suggest new approaches to modulating effects of chronically elevated bile acids in cholestasis [4].
• Deficiency of SHP-1 protein-tyrosine phosphatase in "viable motheaten" mice results in retinal degeneration [5].
• These studies demonstrate that SHP regulates the development of fatty liver by modulating hepatic lipid export, uptake, and synthesis, and that the improved peripheral insulin sensitivity in OB(-/-)/SHP(-/-) mice is associated with decreased hepatic steatosis [6].

Psychiatry related information on Nr0b2

• The SHP complexes were the most reactive toward DNA and produced a greater reduction in the transforming activity of Bacillus subtilis DNA after 3-hr reaction times than did the DDP or DDCP complexes [7].

High impact information on Nr0b2

• In mammalian cells, SHP specifically inhibited transactivation by the superfamily members with which it interacted [8].
• SHP is an orphan member of the nuclear hormone receptor superfamily that contains the dimerization and ligand-binding domain found in other family members but lacks the conserved DNA binding domain [8].
• In the yeast two-hybrid system, SHP interacted with several conventional and orphan members of the receptor superfamily, including retinoid receptors, the thyroid hormone receptor, and the orphan receptor MB67 [8].
• Since specific tyrosine phosphorylation of proteins is important for biological activities induced by chemokines, we examined the role of SHP-1 in functions of chemokines using viable motheaten (me(v)/me(v)) mice that were deficient in SHP-1 [9].
• Mice in which the Lyn, Cd22, or Shp-1 gene has been disrupted have hyperactive B cells and autoantibodies [10].

Chemical compound and disease context of Nr0b2

• Significant increases in the number of lung adenomas in A/J mice were induced by multiple i.p. injections of cis-DDP and each of the DDCP and SHP complexes (total doses, 21 to 108 mumol/kg body weight) [7].

Biological context of Nr0b2

• These results establish a structural model for understanding how SHP interacts with LRH-1 to regulate cholesterol homeostasis and provide new insights into how nuclear receptor/coregulator selectivity is achieved [11].
• Chemotaxis, however, was severely diminished in the SHP-deficient neutrophils relative to control neutrophils, which was possibly attributable to a combination of defective deadhesion and altered actin assembly [12].
• One of these elements contains an estrogen response element half-site that bound purified ERalpha, and ERalpha with a mutated DNA binding domain was unable to stimulate SHP promoter activity [13].
• Finally, we show that the transcriptional repressor SHP (small heterodimer partner) suppressed APOAI gene expression by inhibiting LRH-1 transcriptional activity [14].
• The orphan nuclear receptor ERRgamma is expressed in BAT and its transactivation of the PGC-1alpha promoter is potently inhibited by SHP [1].

Anatomical context of Nr0b2

• It has been shown previously that hepatocyte nuclear factor-4alpha (HNF-4) and the alpha(1)-fetoprotein transcription factor (FTF) are activators of 7alpha-and 12alpha-hydroxylase transcription and that the small heterodimer partner (SHP) suppresses bile acid biosynthesis by heterodimerizing with FTF [15].
• The orphan nuclear receptor SHP regulates PGC-1alpha expression and energy production in brown adipocytes [1].
• In addition, T cell-APC conjugate assays provide direct evidence that a greater proportion of SHP-1-deficient T cells are capable of forming stable conjugates with APCs and this may explain, at least in part, their hyperproliferative response to TCR-triggered stimulation [16].
• As expected from this expression pattern, the activity of the mouse SHP promoter measured by transient transfection was significantly higher in the adrenal-derived Y1 cells than HeLa cells [17].
• Src homology 2 domain-containing protein tyrosine phosphatase (SHP) substrate-1 (SHPS-1) is a transmembrane protein that is expressed predominantly in macrophages [18].

Associations of Nr0b2 with chemical compounds

• Taken together, our results identify a link between lipid and glucose metabolism mediated by the FXR-SHP cascade [19].
• Shp-1 and Shp-2 are cytoplasmic protein tyrosine phosphatases that contain two Src homology 2 (SH2) domains [3].
• Bile acid homeostasis is tightly controlled by the feedback mechanism in which an atypical orphan nuclear receptor (NR) small heterodimer partner (SHP) inactivates several NRs such as liver receptor homologue-1 and hepatocyte nuclear factor 4 [20].
• Cholic acid diet decreased the mRNA levels of these gluconeogenic enzymes, whereas those of SHP were increased [20].
• Furthermore, the expression of FXR target genes, SHP and apoCII, were significantly reduced by LPS (70 and 60%, respectively) [21].

Regulatory relationships of Nr0b2

• The expression of Cyp7a1 and Cyp8b1 is known to be repressed by dietary bile acids via both SHP-dependent and -independent regulations [22].
• In contrast, SHP reporter or BSEP reporter genes were activated to similar degrees by each of the FXR isoforms [23].

Other interactions of Nr0b2

• Here, we report structural and biochemical analyses of the LRH-1/SHP interaction [11].
• Here, we describe the isolation of mouse E1A-like inhibitor of differentiation 1 (EID1) as a candidate coinhibitor for SHP [24].
• Here, we report that bile acids inhibit the expression of gluconeogenic genes, including glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase, and fructose 1,6-bis phosphatase in an SHP-dependent fashion [20].
• We conclude that mice overexpressing Abcb11 display an increase in biliary bile salt secretion and taurodeoxycholate content, which is associated with FXR/SHP-mediated changes in hepatic and ileal gene expression [25].
• Bile acid-induced, farnesoid X receptor (FXR)-mediated induction of the nuclear repressor short heterodimer partner (SHP) has been proposed as a key mechanism reducing Ntcp expression [26].

Analytical, diagnostic and therapeutic context of Nr0b2

• In order to identify the bona fide molecular targets of SHP, we performed global gene expression profiling combined with chromatin immunoprecipitation assays in transgenic mice constitutively expressing SHP in the liver [27].
• Protein and messenger RNA (mRNA) expression of Ntcp and short heterodimer partner (SHP) were analyzed via Western and Northern blotting [28].
• Genomic Southern blot analysis and fluorescence in situ hybridization of human metaphase chromosomes indicated that the SHP gene is located at the human chromosome 1p36.1 subband [17].
• To study the time course for the changes in serum bile acid levels as well as SHP-1 and Ntcp steady-state mRNA levels, mice were subjected to common bile duct ligation (CBDL) for 3, 6, 12, 24, 72, and 168 h and compared with sham-operated controls [29].
• RT-PCR analysis indicated that both LRH-1 and SHP are expressed in human preadipocytes [30].

References