Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P19793 (retinoid X receptor alpha)
 391 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This work describes the molecular mechanisms of fatty acid and hormonal modulations of the retinoid X receptor alpha (RXRalpha) in rat liver cells. We examined the effects of different fatty acids (myristic, stearic, oleic, linolenic, and arachidonic acids, EPA, and the peroxisomal proliferator TTA) and several hormones (the glucocorticoid analogue dexamethasone, insulin, and retinoic acid) on the RXRalpha mRNA and protein levels in rat hepatoma cells and cultured hepatocytes. The fatty acids induced the RXRalpha gene expression resulting in up to 3-fold induction. Dexamethasone alone induced the mRNA level and, in combination with fatty acids, an additive or synergistic effect was observed. The dexamethasone-increased mRNA level was obliterated by insulin. The same pattern of regulation of the protein level was observed when determined in cultured hepatocytes, but the induced protein level showed a lower magnitude of stimulation than the mRNA level. This could indicate a post-transcriptional modulation of the RXRalpha gene expression. Time course studies showed a maximal induction of mRNA and protein levels after 18 h and 48 h, respectively. Our results uniformly show that the RXRalpha gene expression is under distinct regulation by fatty acids and hormones which suggests a coupling with the lipid metabolizing system and the hormonal signaling pathway.
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PMID:Gene transcription of the retinoid X receptor alpha (RXRalpha) is regulated by fatty acids and hormones in rat hepatic cells. 955 40

This report describes a novel adipocyte-like cell line termed 3T3-L1/RB1 that was derived from preadipocyte cell line, 3T3-L1. The 3T3-L1/RB1 cells continued to divide after reaching confluence, formed foci, and constitutively expressed a low level of adipose fatty acid binding protein (A-FABP) mRNA. However, 3T3L-1/RB cells did not undergo terminal differentiation as indicated by the failure of insulin and thiazolidendiones to induce the expression of A-FABP, lipoprotein lipase, and fatty acid synthase. We hypothesized that the 3T3-L1/RB1 variant did not respond to differentiation stimuli because it did not express either peroxisomal proliferator activated receptor gamma2 (PPARgamma2) or its heterodimer partner, retinoid X receptor alpha (RXRalpha). Surprisingly, Western blots revealed that 3T3-L1/ RB1 cells contained both PPARgamma2 and RXRalpha proteins at levels equal to or greater than that of the parent cell line. However, gel retardation assays using the adipose response element from A-FABP and nuclear protein extracts from 3T3-L1/RB1 cells treated with insulin or pioglitazone revealed that nuclear protein extracts from 3T3-L1/RB1 cells had very little ability to bind the PPARgamma2 recognition sequence of the A-FABP gene. These data suggest that the 3T3-L1/RB1 variant contains a mutation that may prevent ligand activation of PPARgamma2, and the subsequent conversion of 3T3-L1/RB1 cells to mature fat cells.
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PMID:A novel 3T3-L1 preadipocyte variant that expresses PPARgamma2 and RXRalpha but does not undergo differentiation. 978 51

Fatty acid transport protein (FATP), a plasma membrane protein implicated in controlling adipocyte transmembrane fatty acid flux, is up-regulated as a consequence of adipocyte differentiation and down-regulated by insulin. Based upon the sequence of the FATP gene upstream region (Hui, T. Y., Frohnert, B. I., Smith, A. J., Schaffer, J. A., and Bernlohr, D. A. (1998) J. Biol. Chem. 273, 27420-27429) a putative peroxisome proliferator-activated receptor response element (PPRE) is present from -458 to -474. To determine whether the FATP PPRE was functional, and responded to lipid activators, transient transfection of FATP-luciferase reporter constructs into CV-1 and 3T3-L1 cells was carried out. In CV-1 cells, FATP-luciferase activity was up-regulated 4- and 5.5-fold, respectively, by PPARalpha and PPARgamma in the presence of their respective activators in a PPRE-dependent mechanism. PPARdelta, however, was unable to mediate transcriptional activation under any condition. In 3T3-L1 cells, the PPRE conferred a small but significant increase in expression in preadipocytes, as well as a more robust up-regulation of FATP expression in adipocytes. Furthermore, the PPRE conferred the ability for luciferase expression to be up-regulated by activators of both PPARgamma and retinoid X receptor alpha (RXRalpha) in a synergistic manner. PPARalpha and PPARdelta activators did not up-regulate FATP expression in 3T3-L1 adipocytes, however, suggesting that these two subtypes do not play a significant role in differentiation-dependent activation in fat cells. Electromobility shift assays showed that all three PPAR subtypes were able to bind specifically to the PPRE as heterodimers with RXRalpha. Nuclear extracts from 3T3-L1 adipocytes also showed a specific gel-shift complex with the FATP PPRE. To correlate the expression of FATP to its physiological function, treatment of 3T3-L1 adipocytes with PPARgamma and RXRalpha activators resulted in an increased uptake of oleate. Moreover, linoleic acid, a physiological ligand, up-regulated FATP expression 2-fold in a PPRE-dependent manner. These results demonstrate that the FATP gene possesses a functional PPRE and is up-regulated by activators of PPARalpha and PPARgamma, thereby linking the activity of the protein to the expression of its gene. Moreover, these results have implications for the mechanism by which certain PPARgamma activators such as the antidiabetic thiazolidinedione drugs affect adipose lipid metabolism.
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PMID:Identification of a functional peroxisome proliferator-responsive element in the murine fatty acid transport protein gene. 993 87

Congenital generalized lipodystrophy (CGL, Berardinelli-Seip Syndrome, OMIM # 269700) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue from birth. Affected individuals have marked insulin resistance, hypertriglyceridemia and acanthosis nigricans, and develop diabetes mellitus during teenage years. The genetic defect for CGL is unknown. A semi-automated genome-wide scan with a set of highly polymorphic short tandem repeats (STR) was carried out in 17 well-characterized pedigrees and identified a locus for CGL to chromosome 9q34. The maximum two-point lod score obtained was 3.6 at D9S1818 (theta(max) = 0.05). There was evidence for genetic heterogeneity (alpha = 0.73) and 2 of the pedigrees were unlinked. Multipoint linkage analysis excluding the 2 unlinked families yielded a peak lod score of 5.4 between loci D9S1818 and D9S1826. The CGL1 critical region harbors a plausible candidate gene encoding the retinoid X receptor alpha (RXRA) that plays a central role in adipocyte differentiation. Identification of the CGL gene(s) will contribute to our understanding of the adipocyte differentiation and elucidation of the mechanisms of insulin resistance in disorders of adipose tissue.
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PMID:A gene for congenital generalized lipodystrophy maps to human chromosome 9q34. 1048 16

Insulin-like growth factor binding protein-3 (IGFBP-3), the major circulating carrier protein for IGFs, is also active in the cellular environment as a potent antiproliferative agent. It appears to function both by cell cycle blockade and the induction of apoptosis. Transfection of p53 negative T47D breast cancer cells to express IGFBP-3 leads to induction of the apoptotic protein bax and an increase in sensitivity to ionising radiation. IGFBP-3 can be transported to the nucleus by an importin beta mediated mechanism, where it has been shown to interact with the retinoid X receptor alpha and possibly other nuclear elements. Expression of oncogenic ras is associated with resistance to exogenous IGFBP-3, the effect being reversible by inhibition of mitogen activated protein (MAP) kinase phosphorylation. IGFBP-3 antiproliferative signalling appears to require an active transforming growth factor beta (TGF-beta) signalling pathway, and IGFBP-3 stimulates phosphorylation of the TGF-beta signalling intermediates Smad2 and Smad3. These recent findings all point to a complex intracellular mode of action of IGFBP-3, which will need to be better understood if anti-cancer treatments are to take advantage of the antiproliferative activity of IGFBP-3.
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PMID:Signalling pathways involved in antiproliferative effects of IGFBP-3: a review. 1137 25

Insulin-like growth factor (IGF) binding protein (IGFBP)-3 has been shown to be a growth inhibitory, apoptosis-inducing molecule by virtue of its ability to bind IGFs, in addition to previously demonstrated IGF-independent effects. The recent discovery of the interaction between nuclear IGFBP-3 and 9-cis retinoic acid receptor-alpha (retinoid X receptor alpha RXRalpha), a nuclear receptor, and its involvement in the regulation of transcriptional signaling and apoptosis represents an important paradigm shift in the understanding of IGFBP function. RXRalpha is required for the apoptosis-inducing effects of IGFBP-3. IGFBP-3 and RXR ligands are additive in inducing apoptosis in cancer cells. IGFBP-3 has direct effects on gene transcription, as RXR response element reporter signaling was enhanced and the all-trans retinoic acid receptor response element reporter signaling was inhibited. Accumulating evidence further confirms IGF-independent functions of this multifunction binding protein. Other binding proteins, in addition to other members of the IGF axis, have now been described in the nucleus and are postulated to have effects on transcriptional events. Investigation into these new interactions will expose new protein partners in the interface between the nuclear receptor and growth factor pathways and reveal new targets to be exploited in the treatment of cancer and other diseases.
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PMID:Nuclear effects: unexpected intracellular actions of insulin-like growth factor binding protein-3. 1237 88

The forkhead factor Foxo1 (or FKHR) was identified in a yeast two-hybrid screen as a peroxisome proliferator-activated receptor (PPAR) gamma-interacting protein. Foxo1 antagonized PPARgamma activity and vice versa indicating that these transcription factors functionally interact in a reciprocal antagonistic manner. One mechanism by which Foxo1 antagonizes PPARgamma activity is through disruption of DNA binding as Foxo1 inhibited the DNA binding activity of a PPARgamma/retinoid X receptor alpha heterodimeric complex. The Caenorhabditis elegans nuclear hormone receptor, DAF-12, interacted with the C. elegans forkhead factor, DAF-16, paralleling the interaction between PPARgamma and Foxo1. daf-12 and daf-16 have been implicated in C. elegans insulin-like signaling pathways, and PPARgamma and Foxo1 likewise have been linked to mammalian insulin signaling pathways. These results suggest a convergence of PPARgamma and Foxo1 signaling that may play a role in insulin action and the insulinomimetic properties of PPARgamma ligands. A more general convergence of nuclear hormone receptor and forkhead factor pathways may be important for multiple biological processes and this convergence may be evolutionarily conserved.
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PMID:Convergence of peroxisome proliferator-activated receptor gamma and Foxo1 signaling pathways. 1296 85

Compensatory hyperinsulinemia stemming from peripheral insulin resistance is a well-recognized metabolic disturbance that is at the root cause of diseases and maladies of Syndrome X (hypertension, type 2 diabetes, dyslipidemia, coronary artery disease, obesity, abnormal glucose tolerance). Abnormalities of fibrinolysis and hyperuricemia also appear to be members of the cluster of illnesses comprising Syndrome X. Insulin is a well-established growth-promoting hormone, and recent evidence indicates that hyperinsulinemia causes a shift in a number of endocrine pathways that may favor unregulated tissue growth leading to additional illnesses. Specifically, hyperinsulinemia elevates serum concentrations of free insulin-like growth factor-1 (IGF-1) and androgens, while simultaneously reducing insulin-like growth factor-binding protein 3 (IGFBP-3) and sex hormone-binding globulin (SHBG). Since IGFBP-3 is a ligand for the nuclear retinoid X receptor alpha, insulin-mediated reductions in IGFBP-3 may also influence transcription of anti-proliferative genes normally activated by the body's endogenous retinoids. These endocrine shifts alter cellular proliferation and growth in a variety of tissues, the clinical course of which may promote acne, early menarche, certain epithelial cell carcinomas, increased stature, myopia, cutaneous papillomas (skin tags), acanthosis nigricans, polycystic ovary syndrome (PCOS) and male vertex balding. Consequently, these illnesses and conditions may, in part, have hyperinsulinemia at their root cause and therefore should be classified among the diseases of Syndrome X.
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PMID:Hyperinsulinemic diseases of civilization: more than just Syndrome X. 1452 33

Fatty acids (FAs) are known to be important regulators of insulin secretion from pancreatic beta-cells. FA-coenzyme A esters have been shown to directly stimulate the secretion process, whereas long-term exposure of beta-cells to FAs compromises glucose-stimulated insulin secretion (GSIS) by mechanisms unknown to date. It has been speculated that some of these long-term effects are mediated by members of the peroxisome proliferator-activated receptor (PPAR) family via an induction of uncoupling protein-2 (UCP2). In this study we show that adenoviral coexpression of PPARalpha and retinoid X receptor alpha (RXRalpha) in INS-1E beta-cells synergistically and in a dose- and ligand-dependent manner increases the expression of known PPARalpha target genes and enhances FA uptake and beta-oxidation. In contrast, ectopic expression of PPARgamma/RXRalpha increases FA uptake and deposition as triacylglycerides. Although the expression of PPARalpha/RXRalpha leads to the induction of UCP2 mRNA and protein, this is not accompanied by reduced hyperpolarization of the mitochondrial membrane, indicating that under these conditions, increased UCP2 expression is insufficient for dissipation of the mitochondrial proton gradient. Importantly, whereas expression of PPARgamma/RXRalpha attenuates GSIS, the expression of PPARalpha/RXRalpha potentiates GSIS in rat islets and INS-1E cells without affecting the mitochondrial membrane potential. These results show a strong subtype specificity of the two PPAR subtypes alpha and gamma on lipid partitioning and insulin secretion when systematically compared in a beta-cell context.
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PMID:Peroxisome proliferator-activated receptor alpha (PPARalpha) potentiates, whereas PPARgamma attenuates, glucose-stimulated insulin secretion in pancreatic beta-cells. 1600 73

Pyruvate carboxylase (PC) plays a crucial role in various metabolic pathways, including gluconeogenesis, lipogenesis, and glucose-induced insulin secretion. Here we showed for the first time that the PC gene is transcriptionally regulated by peroxisome proliferator-activated receptor-gamma (PPARgamma) in vitro and in vivo in white and brown adipose tissue. PC mRNA and protein are markedly increased during differentiation of 3T3-L1 cells and HIB-1B, in parallel with the expression of the adipogenic transcription factors, CCAAT-enhancer binding protein alpha, PPARgamma1, and PPARgamma2. Tumor necrosis factor-alpha, a cytokine that blocks differentiation of 3T3-L1 cells, suppressed PC expression. Co-transfection studies in 3T3-L1 preadipocytes or HEK293T cells with a 2.3-kb promoter fragment of mouse PC gene linked to a luciferase reporter construct and with plasmids overexpressing retinoid X receptor alpha/PPARgamma1 or retinoid X receptor alpha/PPARgamma2 showed a 6-8-fold increase above the basal promoter activity. Furthermore, treatment of these transfected cells with the PPARgamma agonist doubled the promoter activity. Mutation of the putative PPAR-response element-(-386/-374) of this 2.3-kb PC promoter fragment abolished the PPARgamma response. Gel shift and chromatin immunoprecipitation assays demonstrated that endogenous PPARgamma binds to this functional PPAR-response element of the PC promoter. Mice with targeted disruption of the PPARgamma2 gene displayed approximately 50-60% reduction of PC mRNA and protein in white adipose tissue. Similarly, in brown adipose tissue of PPARgamma2-deficient mice subjected to cold exposure, PC mRNA was 40% lower than that of wild type mice. Impaired in vitro differentiation of white adipocytes of PPARgamma2 knock-out mice was also associated with a marked reduction of PC mRNA. Our findings identified PC as a PPARgamma-regulated gene and suggested a role for PPARgamma regulating intermediary metabolism.
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PMID:The peroxisome proliferator-activated receptor-gamma regulates murine pyruvate carboxylase gene expression in vivo and in vitro. 1591 42


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