Disease relevance of Nr5a2

• However, whether inflammatory cytokines or elevated bile acid levels increased Lrh-1/Mrp3 expression in obstructive cholestasis was not known [1].
• Haploinsufficiency of LRH-1 blunts intestinal tumorigenesis in the ApcMin/+ mice, a genetic model of intestinal cancer [2].
• Alterations in LRH-1 expression and/or activity in adipose tissue could therefore have considerable effects on local estrogen production and breast cancer development [3].
• Taken together, our results outline an unexpected role for LRH-1 in the modulation of the hepatic acute-phase response [4].
• These findings underscore the importance of LRH-1 in the control of intestinal inflammation and the pathogenesis of inflammatory bowel disease [5].

High impact information on Nr5a2

• LRH-1 is an orphan nuclear receptor predominantly expressed in tissues of endodermal origin, where it controls development and cholesterol homeostasis [6].
• Mutating the conserved arginine in helix 2 reduced LRH-1 receptor activity and coregulator recruitment, consistent with the partial loss-of-function phenotype exhibited by an analogous SF-1 human mutant [7].
• Here, we report structural and biochemical analyses of the LRH-1/SHP interaction [8].
• LRH-1 gene expression is reduced in tumors that express elevated levels of the proinflammatory cytokine TNF-alpha [2].
• Reciprocally, decreased LRH-1 expression in Lrh-1+/- mice attenuates TNF-alpha expression [2].

Biological context of Nr5a2

• FTF recognizes the DNA sequence 5'-TCAAGGTCA-3', the canonical recognition motif for FTZ-F1 receptors. cDNA sequence homologies indicate that rat FTF is the ortholog of mouse LRH-1 and Xenopus xFF1rA [9].
• Amino acid substitutions revealed that Ad4BP/SF-1 and LRH-1 preferentially interact with L(+1)XXLL-related motifs containing serine, tyrosine, serine, and threonine at positions -2, +2, +3, and +6, respectively [10].
• In this report, we use mutagenesis and reporter gene assays to carry out a detailed analysis on the hinge region and the proximal ligand binding domain (LBD) of human (h) LRH-1 that possess important regulatory functions [11].
• These results indicate that induction of Mrp3 after BDL is due to Tnfalpha-dependent up-regulation of Lrh-1 [1].
• The combined treatment of forskolin and phorbol ester (which mimic PGE2) as well as LRH-1, which maximally induced reporter gene expression (140-fold), was also completely inhibited by SHP [12].

Anatomical context of Nr5a2

• In vitro and in vivo results show that LRH-1 plays an essential role in the maintenance of Oct4 expression in ES cells at the epiblast stage of embryonic development, thereby maintaining pluripotence at this crucial developmental stage prior to segregation of the primordial germ cell lineage at gastrulation [13].
• LRH-1 protein was found in Caco-2 cells and mouse ileum, but not IEC-6 cells or rat ileum [14].
• LRH-1 expression was first detected in the urogenital ridge before sexual determination, in primordial germ cells and surrounding somatic cells; expression persisted after differentiation into testes and ovaries [15].
• Of interest, LRH-1 expression declined in the developing ovary and testis at embryonic day 15.5 but increased again just after birth in the ovary in granulosa cells and transiently in oocytes of developing follicles [15].
• However, OR2.0 consists of 2945 bp, is expressed in the livers and the adrenal glands, and is considered to be the chicken counterpart of mouse LRH-1, which is a member of the FTZ-F1 family in mammals [16].

Associations of Nr5a2 with chemical compounds

• Likewise, Lrh-1+/- mice are protected against the formation of aberrant crypt foci in the colon of mice exposed to the carcinogen azoxymethane [2].
• In support of this hypothesis, we show that 9-cis-retinoic acid, acting through RXR, inhibits both the basal and PGC-1alpha-induced transcriptional activity of LRH-1 [17].
• METHODS: Expression of LRH-1 mRNA in juvenile (30 days old) and adult (60 days old) mouse brain was examined using non-radioactive in situ hybridization with digoxigenin labeled cRNA probes and with RT PCR using specific primers [18].
• LRH-1 expression was found to be abundant and highly restricted to cells involved in estrogen biosynthesis-granulosa cells during the estrous cycle, and in corpora lutea (CL) of pregnancy [19].
• GATA factors and the nuclear receptors, steroidogenic factor 1/liver receptor homolog 1, are key mutual partners in the regulation of the human 3beta-hydroxysteroid dehydrogenase type 2 promoter [20].
• LRH-1 deficiency in either tissue changed mRNA levels of genes involved in cholesterol and bile acid homeostasis [21].

Co-localisations of Nr5a2

• LRH-1 is colocalized with Oct4 in the inner cell mass and the epiblast of embryos at early developmental stages [13].

Other interactions of Nr5a2

• Ostalpha and Ostbeta promoter activities were increased by coexpression of LRH-1 and decreased by coexpression of SHP [22].
• Sequence analysis revealed potential cis-acting elements for farnesoid X receptor (FXR) and liver receptor homolog-1 (LRH-1) in the mouse Ostalpha and Ostbeta promoters and reporter constructs containing Ostalpha and Ostbeta 5'-flanking sequences were positively regulated by bile acids [22].
• Tumor necrosis factor alpha-dependent up-regulation of Lrh-1 and Mrp3(Abcc3) reduces liver injury in obstructive cholestasis [1].
• Orphan nuclear receptor LRH-1 is required to maintain Oct4 expression at the epiblast stage of embryonic development [13].

Analytical, diagnostic and therapeutic context of Nr5a2

• RT-PCR analysis indicated that both LRH-1 and SHP are expressed in human preadipocytes [12].
• Quantitative real-time PCR revealed that LRH-1 (but not SF-1) is expressed in the preadipocyte fraction of human adipose tissue at levels comparable with that of liver [3].
• Chromatin immunoprecipitation experiments revealed that LRH-1 binds to the human APO AI promoter in vivo [23].
• Electrophoretic mobility shift assays and chromatin immunoprecipitation analysis showed that PDX-1 bound to the LRH-1 promoter, both in cultured cells in vitro and during pancreatic development in vivo [24].

References