Disease relevance of Nrip1

• Over-expression of receptor interacting protein 140 (RIP140) suppressed thyroid hormone (T3) induction of cellular retinoic acid binding I protein (CRABPI) gene in P19 embryonal carcinoma cells [1].
• RIP140-null mice, previously reported to resist weight gain on a high-fat diet, are shown here to display enhanced glucose tolerance and enhanced responsiveness to insulin compared with matched wild-type mice upon high-fat feeding [2].
• Mice devoid of the corepressor protein RIP140 are lean, show resistance to high-fat diet-induced obesity and hepatic steatosis, and have increased oxygen consumption [3].
• The association of the RIP140 protein with the superfamily of nuclear receptors may be of significance in studies of trisomy 21 (Down syndrome) and Alzheimers disease, since a modifier locus has been speculated to reside on 21q11 [4].
• No phosphopeptides were detected on RIP140 expressed in E. coli in a parallel experiment, suggesting that RIP140 phosphorylation occurred specifically only in eukaryotic cells [5].

High impact information on Nrip1

• Here we show that the co-repressor nuclear-receptor-interacting protein 1 (Nrip1; encoded by the gene Nrip1) is essential for ovulation [6].
• The nuclear receptor co-repressor nrip1 (RIP140) is essential for female fertility [6].
• Here we report that a short sequence motif LXXLL (where L is leucine and X is any amino acid) present in RIP-140, SRC-1 and CBP is necessary and sufficient to mediate the binding of these proteins to liganded nuclear receptors [7].
• Using an siRNA-based screen, we identified the transcriptional corepressor RIP140 as a negative regulator of insulin-responsive hexose uptake and oxidative metabolism in 3T3-L1 adipocytes [2].
• Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes [2].

Biological context of Nrip1

• Therefore, whereas the pre-ovulatory surge of luteinizing hormone induces both ovulation and luteinization, the ability to suppress the action of nuclear receptors is essential for the coordinated control of ovarian function with the essential process of oocyte release dependent on the activity of the transcriptional co-repressor Nrip1 (RIP40) [6].
• T3 treatment resulted in elevated histone acetylation of the endogenous CRABPI gene promoter, but simultaneous expression of RIP140 resulted in significantly reduced histone acetylation of this promoter, primarily through the recruitment of HDAC4 [1].
• By performing both embryo and ovarian transfer experiments we demonstrate that, provided the block to ovulation is by-passed, Nrip1(-/-) mice are capable of establishing and maintaining pregnancies [8].
• Consistent with these microarray data, RIP140 gene silencing in cultured adipocytes increased both conversion of [14C]glucose to CO2 and mitochondrial oxygen consumption [2].
• We conclude that RIP140 is a major suppressor of adipocyte oxidative metabolism and mitochondrial biogenesis, as well as a negative regulator of whole-body glucose tolerance and energy expenditure in mice [2].

Anatomical context of Nrip1

• It also indicated a temporal regulation of Nrip1 in the corpora lutea at different stages of pregnancy, with increased levels at midgestation at approximately d 9.5 postcoitum (pc) [8].
• Expression analysis indicated that Nrip1 is present in the uterus in stromal and glandular epithelial cells, primary decidual cells, and subsequently in differentiating decidual cells at the anti-mesometrial side of the implantation site [8].
• Conversely, we show that reexpression of RIP140 in mouse embryonic fibroblasts derived from RIP140-null mice downregulates expression of many of these same genes [2].
• Therefore, the maintenance of energy homeostasis requires the action of a transcriptional repressor in white adipose tissue, and ligand-dependent recruitment of RIP140 to nuclear receptors may provide a therapeutic target in the treatment of obesity and related disorders [3].
• 3. Here, we report the mapping of the gene for receptor interacting protein 140 (RIP140) on 21q11 by means of YACs, PACs and hybrid cell lines [4].

Associations of Nrip1 with chemical compounds

• Receptor interacting protein 140 as a thyroid hormone-dependent, negative co-regulator for the induction of cellular retinoic acid binding protein I gene [1].
• In addition, RIP140 suppressed the retinoic acid (RA) receptor-mediated RA induction in a dose-dependent manner [9].
• Characterization of receptor-interacting protein 140 in retinoid receptor activities [10].
• In contrast to the wild-type protein, constitutively active receptors were able to bind both the receptor-interacting protein RIP-140 and the steroid receptor co-activator SRC-1 in a ligand-independent manner, although in the case of SRC-1 this was only evident when the receptors were prebound to DNA [11].
• We demonstrate that RIP140 is required for the ability of LXR to repress the expression of the phosphoenolpyruvate carboxykinase gene in Fao cells and mice [12].

Other interactions of Nrip1

• Analysis of the Ucp1 promoter showed RIP140 recruitment to a key enhancer element, demonstrating a direct role in repressing gene expression [13].
• Mechanistically, RIP140 was found to require the nuclear receptor ERRalpha to regulate hexose uptake and mitochondrial proteins SDHB and CoxVb, although it likely acts through other nuclear receptors as well [2].
• RIP140 (receptor interacting protein with a molecular weight of 140 kDa) is a widely expressed corepressor that has the potential to inhibit the transcriptional activity of most, if not all nuclear receptors [14].

Analytical, diagnostic and therapeutic context of Nrip1

• In co-immunoprecipitation and chromatin immunoprecipitation assays, RIP140 formed complexes with T3R/RXR in solution and on the endogenous target, the CRABPI promoter [1].
• To identify genes that may be subject to regulation by RIP140 or play a role in ovulation, we compared ovarian gene expression profiles in untreated immature wild-type and RIP140 null mice and after treatment with pregnant mare serum gonadotropin and human chorionic gonadotropin [15].
• To determine which ovarian cell types express SRC-1, RIP140, and SPA, in situ hybridization was performed on sheep ovaries [16].
• Embryo transfer experiments and ovarian transplantation identify the ovary as the only site in which nuclear receptor interacting protein 1/RIP140 action is crucial for female fertility [8].

References