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PubMed2001

Up-regulation of endothelial nitric oxide synthase through beta(2)-adrenergic receptor--the role of a beta-blocker with NO-releasing action.

We determined the existence and role of beta(2)-adrenergic receptor in cultured BAECs through the effect of a beta-blocker having NO releasing action; 3,4-dihydro-8(2-hydroxy-3-isopropylamino)-propoxy-3-nitroxy-2H-1-benzopyran; nipradilol on eNOS and eNOS regulatory protein caveolin-1. beta(2) receptor exists in BAECs. eNOS mRNA and protein were up-regulated by its treatment whereas those of caveolin were not altered considerably. This eNOS up-regulatory action was abolished by beta(2) receptor antagonist, ICI-118551. Increase of NO metabolites, protein and mRNA of eNOS was also partially inhibited by co-treatment of NOS inhibitor, L-NA with nipradilol. This is the first investigation of the action of non-selective beta blocker on eNOS through beta(2) receptor. The drug increases NO on incubation with BAECs about 50% as a NO donor and about 50% as results of eNOS up-regulation.

Adrenergic beta-Antagonists↗
PubMed2002

Involvement of Na(+)/Ca(2+) exchanger in endothelial NO production and endothelium-dependent relaxation.

Endothelial nitric oxide (NO) synthase (eNOS) is controlled by Ca(2+)/calmodulin and caveolin-1 in caveolae. It has been recently suggested that Na(+)/Ca(2+) exchanger (NCX), also expressed in endothelial caveolae, is involved in eNOS activation. To investigate the role played by NCX in NO synthesis, we assessed the effects of Na(+) loading (induced by monensin) on rat aortic rings and cultured porcine aortic endothelial cells. Effect of monensin was evaluated by endothelium-dependent relaxation of rat aortic rings in response to acetylcholine and by real-time measurement of NO release from cultured endothelial cells stimulated by A-23187 and bradykinin. Na(+) loading shifted the acetylcholine concentration-response curve to the left. These effects were prevented by pretreatment with the NCX inhibitors benzamil and KB-R7943. Monensin potentiated Ca(2+)-dependent NO release in cultured cells, whereas benzamil and KB-R7943 totally blocked Na(+) loading-induced NO release. These findings confirm the key role of NCX in reverse mode on Ca(2+)-dependent NO production and endothelium-dependent relaxation.

Acetylcholine↗
PubMed2005

Caveolae targeting and regulation of large conductance Ca(2+)-activated K+ channels in vascular endothelial cells.

The vascular endothelium is richly endowed with caveolae, which are specialized membrane microdomains that facilitate the integration of specific cellular signal transduction processes. We found that the large conductance Ca(2+)-activated K+ (BK) channels are associated with caveolin-1 in bovine aortic endothelial cells (BAECs). OptiPrep gradient cell fractionation demonstrated that BK channels were concentrated in the caveolae-rich fraction in BAECs. Immunofluorescence imaging showed co-localization of caveolin-1 and BK channels in the BAEC membrane. Immunoprecipitation and glutathione S-transferase pull-down assay results indicated that caveolin-1 and BK channels are physically associated. However, whole cell patch clamp recordings could not detect BK (iberiotoxin-sensitive) currents in cultured BAECs under baseline conditions, even though the presence of BK mRNA and protein expression was confirmed by reverse transcription-PCR and Western blots. Cholesterol depletion redistributed the BK channels to non-caveolar fractions of BAECs, resulting in BK channel activation (7.3 +/- 1.6 pA/picofarad (pF), n = 5). BK currents were also activated by isoproterenol (ISO, 1 microM, 6.9 +/- 2.4 pA/pF, n = 6). Inclusion of a caveolin-1 scaffolding domain peptide (10 microM) in the pipette solution completely abrogated the effects of ISO on BK channel activation, whereas inclusion of the scrambled control peptide (10 microM) did not inhibit the ISO effects. We have also found that caveolin-1 knockdown by small interference RNA activated BK currents (5.3 +/- 1.4 pA/pF, n = 6). We conclude that: 1) BK channels are targeted to caveolae microdomains in vascular endothelial cells; 2) caveolin-1 interacts with BK channels and exerts a negative regulatory effect on channel functions; and 3) BK channels are inactive under control conditions but can be activated by cholesterol depletion, knockdown of caveolin-1 expression, or ISO stimulation. These novel findings may have important implications for the role of BK channels in the regulation of endothelial function.

Amino Acid Sequence↗
PubMed2004

High-mobility group A1a protein regulates Ras/ERK signaling in MCF-7 human breast cancer cells.

High-mobility group (HMG) A1 proteins are gene regulatory factors whose overexpression is frequently observed in naturally occurring human cancers. The overexpression of transgenic HMGA1 proteins in cells results in neoplastic transformation and promotes progression to malignant cellular phenotypes. To understand the underlying molecular and biological events involved in these phenomena, we used oligonucleotide microarray analyses to generate an HMGA1a-induced expression profile for approximately 22,000 genes. This gene expression profile was generated using a well-characterized transgenic human MCF-7 mammary adenocarcinoma cell line in which overexpression of transgenic HMGA1 promotes a transition to a more malignant and metastatic phenotype. Microarray expression analyses, together with independent quantitative real-time reverse transcriptase polymerase chain reaction results, indicate that HMGA1a regulates genes involved in the Ras-extracellular signal-related kinase (Ras/ERK) mitogenic signaling pathway, including KIT ligand and caveolins 1 and 2. We also found that many cholesterol biosynthesis genes were decreased in cells overexpressing HMGA1a. Cholesterol depletion, decreased caveolin, and increased KIT ligand expression, are all independently associated with the activation of Ras/ERK signaling. Upon further analysis, we found that sensitivity to epidermal growth factor activation of ERK phosphorylation was significantly higher, and that cholesterol was significantly depleted, in cells overexpressing HMGA1a. The cumulative evidence indicates that one likely mechanism by which the HMGA1a protein promotes malignant changes in cells is through increased sensitivity to the activation of the Ras/ERK signaling pathway.

Animals↗
PubMed2001

Nitric oxide attenuates signal transduction: possible role in dissociating caveolin-1 scaffold.

Caveolae harbor different serpentine receptors, intracellular components of signaling cascades, and certain enzymes, including endothelial nitric oxide synthase (eNOS). The regulation of eNOS activity by Ca(2+)/calmodulin and caveolin has been described. We have previously demonstrated that nitric oxide (NO) can modulate signaling initiated via receptors localized to caveolae. In the present study, we show that NO donors induced an increase in the monomeric form of this scaffolding protein in cultured endothelial cells, the effect mimicked by 8-bromo cGMP. Proximity imaging of endothelial cells transfected with the thermotolerant green fluorescent protein-caveolin-1 construct demonstrated that sodium nitroprusside resulted in the increased fluorescence ratio of 410:470 nm, consistent with the distancing of fluorescently tagged caveolin-1. Pulse labeling of endothelial cells with cholera toxin B subunit indicated that sodium nitroprusside reversibly decreased its binding. Signaling via G protein-coupled receptors resident to caveolae was inhibited by pretreatment with NO donor. The data demonstrate that NO modulation of cell signaling is accomplished in part by regulating the state of caveolin-1 oligomerization. NO-induced attenuation of signaling involves reversible dissociation of caveolin scaffold, thus providing both spatial and temporal modulation of signal transduction.

Animals↗
PubMed1998

Water channel proteins in rat cardiac myocyte caveolae: osmolarity-dependent reversible internalization.

We show by confocal immunofluorescence microscopy that the water channel protein aquaporin-1, not previously identified within cardiomyocytes, localizes at 20 and 37 degrees C to rat cardiomyocyte sarcolemmal caveolar membrane and subsarcolemmal cytoplasm of primary atrial myocyte cultures, dissociated atrial and ventricular myocytes, and in situ cardiomyocytes of atrial and ventricular frozen sections. Confocal immunofluorescence microscopy shows that the normal in situ colocalization of the quasi-muscle-specific caveolar coating protein caveolin-3 with aquaporin-1 is reversibly disrupted by exposing in situ atrial or ventricular myocytes to physiological saline made hypertonic by adding 150 mM sucrose or 75 mM NaCl to isotonic physiological saline. This causes caveolae to close off from the interstitium and swell, while aquaporin-1 is internalized reversibly. At 4 degrees C aquaporin-1 does not colocalize with caveolin-3. We suggest that 1) in vivo, under near-isotonic conditions, caveolae may alternate frequently between brief open and closed-off states; 2) aquaporin-1-caveolin-3 colocalization may be energy dependent; and 3) while closed off from the interstitium, each caveola transiently functions as an osmometer that experiences, monitors, and reacts to net water flow from or into the subcaveolar cytosol of the myocyte.

Animals↗
PubMed1999

Depalmitoylation of endothelial nitric-oxide synthase by acyl-protein thioesterase 1 is potentiated by Ca(2+)-calmodulin.

Protein palmitoylation represents an important mechanism governing the dynamic subcellular localization of many signaling proteins. Palmitoylation of endothelial nitric-oxide synthase (eNOS) promotes its targeting to plasmalemmal caveolae; agonist-promoted depalmitoylation leads to eNOS translocation. Depalmitoylation and translocation of eNOS modulate the agonist response, but the pathways that regulate eNOS palmitoylation and depalmitoylation are poorly understood. We now show that the newly characterized acyl-protein thioesterase 1 (APT1) regulates eNOS depalmitoylation. Immunoblot analyses indicate that APT1 is expressed in bovine aortic endothelial cells, which express eNOS. APT1 overexpression appears to accelerate the depalmitoylation of eNOS in COS-7 cells cotransfected with eNOS and APT1 cDNAs. Additionally, purified recombinant APT1 depalmitoylates eNOS assayed in biological membranes isolated from endothelial cells biosynthetically labeled with [(3)H]palmitate or COS-7 cells transfected with eNOS cDNA. More important, the APT1-catalyzed depalmitoylation of palmitoyl-eNOS is potentiated by Ca(2+)-calmodulin (CaM), a key allosteric activator of eNOS. In contrast, APT1-catalyzed depalmitoylation of the G protein Galpha(s) is unaffected by Ca(2+)-CaM. Furthermore, caveolin, a palmitoylated membrane protein, does not appear to be a substrate for APT1. Taken together, these results support a role for APT1 in the regulation of eNOS depalmitoylation and suggest that Ca(2+)-CaM activation of eNOS renders the enzyme more susceptible to APT1-catalyzed depalmitoylation.

Animals↗
PubMed2004

1,1-Bis(3'-indolyl)-1-(p-substitutedphenyl)methanes induce peroxisome proliferator-activated receptor gamma-mediated growth inhibition, transactivation, and differentiation markers in colon cancer cells.

1,1-Bis(3'indolyl)-1-(p-substitutedphenyl)methanes containing p-trifluoromethyl (DIM-C-pPhCF)), p-t-butyl (DIM-C-pPhtBu), and p-phenyl (DIM-C-pPhC6H5) groups induce peroxisome proliferator-activated receptor gamma (PPARgamma)-mediated transactivation in HT-29, HCT-15, RKO, and SW480 colon cancer cell lines. Rosiglitazone also induces transactivation in these cell lines and inhibited growth of HT-29 cells, which express wild-type PPARgamma but not HCT-15 cells, which express mutant (K422Q) PPARgamma. In contrast, DIM-C-pPhCF3, DIM-C-pPhtBu, and DIM-C-pPhC6H5 inhibited growth of both HT-29 and HCT-15 cells with IC50 values ranging from 1 to 10 micromol/L. Rosiglitazone and diindolylmethane (DIM) analogues did not affect expression of cyclin D1, p21, or p27 protein levels or apoptosis in HCT-15 or HT-29 cells but induced keratin 18 in both cell lines. However, rosiglitazone induced caveolins 1 and 2 in HT-29 but not HCT-15 cells, whereas these differentiation markers were induced by DIM-C-pPhCF3 and DIM-C-pPhC6H5 in both cell lines. Because overexpression of caveolin 1 is known to suppress colon cancer cell and tumor growth, the growth inhibitory effects of rosiglitazone and the DIM compounds are associated with PPARgamma-dependent induction of caveolins.

Apoptosis↗
PubMed2003

Chinese hamster ovary K2 cell lipid droplets appear to be metabolic organelles involved in membrane traffic.

The principal lipids in animal cell lipid droplets are cholesterol, cholesterol ester, and triglyceride, but the protein composition of this compartment is largely unknown. Here we report on the proteomic analysis of lipid droplets. Using a combination of mass spectrometry and immunoblotting, we identify nearly 40 specifically associated proteins in droplets isolated from Chinese hamster ovary K2 cells grown in normal medium. The proteins fall in to five groups: structural molecules of the droplet-like adipose differentiation-related protein; multiple enzymes involved in the synthesis, storage, utilization, and degradation of cholesterol esters and triglycerides; multiple, different Rab GTPases known to be involved in regulating membrane traffic; signaling molecules such as p50RhoGAP; and a group of proteins that do not fit any classification but include proteins often found in caveolae/rafts such as caveolin-1 and 2 and flotillin-1. The proteome of droplets isolated from cells grown in the presence of oleate is largely the same except for an increase in the amount of adipose differentiation-related protein, caveolin-1, and a protein thought to be involved in phospholipid recycling called CGI-58. Based on the protein profile, the lipid droplet appears to be a complex, metabolically active organelle that is directly involved in membrane traffic and possibly phospholipid recycling. We propose the name adiposome for this organelle.

Animals↗
PubMed2001

Caveolin-2 is targeted to lipid droplets, a new "membrane domain" in the cell.

Caveolin-1 and -2 constitute a framework of caveolae in nonmuscle cells. In the present study, we showed that caveolin-2, especially its beta isoform, is targeted to the surface of lipid droplets (LD) by immunofluorescence and immunoelectron microscopy, and by subcellular fractionation. Brefeldin A treatment induced further accumulation of caveolin-2 along with caveolin-1 in LD. Analysis of mouse caveolin-2 deletion mutants revealed that the central hydrophobic domain (residues 87-119) and the NH(2)-terminal (residues 70-86) and COOH-terminal (residues 120-150) hydrophilic domains are all necessary for the localization in LD. The NH(2)- and COOH-terminal domains appeared to be related to membrane binding and exit from ER, respectively, implying that caveolin-2 is synthesized and transported to LD as a membrane protein. In conjunction with recent findings that LD contain unesterified cholesterol and raft proteins, the result implies that the LD surface may function as a membrane domain. It also suggests that LD is related to trafficking of lipid molecules mediated by caveolins.

Animals↗
PubMed2001

Temporal effects of 17beta-estradiol on caveolin-1 mRNA and protein in bovine aortic endothelial cells.

Endothelial nitric oxide synthase (eNOS) is regulated both by caveolin-1 and 17beta-estradiol (E(2)). Temporal relationships between effects of estrogen on caveolin-1 and nitric oxide (NO) are not known. Therefore, this study was designed to determine whether estrogen regulates caveolin-1 and, if so, whether such regulation corresponds to changes in nitrite/nitrate (NO(x)) production. Bovine aortic endothelial cells (BAECs) were cultured in the absence and presence of 17beta-estradiol or 17alpha-estradiol (10(-8) and 10(-10) M) for 12, 24, and 48 h. eNOS protein expression and NO(x) production increased significantly after 24 h but not after 12-h treatment with 17beta- and not 17alpha-estradiol. Both mRNA and protein for caveolin-1 were increased significantly only after 48-h treatment with E(2), but eNOS protein and NO(x) production were decreased compared with cells treated for 24 h. These increases in caveolin-1 were inhibited by the estrogen receptor antagonist ICI-182,780 (10(-6) M). Results of this study suggest that E(2) stimulates caveolin-1 transcription and translation through estrogen receptor-mediated mechanisms. The results further suggest that estrogen may indirectly regulate NO(x) through caveolin-1 expression, which inhibits eNOS catalytic activity.

Animals↗
PubMed2001

Cross-talk between caveolae and glycosylphosphatidylinositol-rich domains.

Most mammalian cells have in their plasma membrane at least two types of lipid microdomains, non-invaginated lipid rafts and caveolae. Glycosylphosphatidylinositol (GPI)-anchored proteins constitute a class of proteins that are enriched in rafts but not caveolae at steady state. We have analyzed the effects of abolishing GPI biosynthesis on rafts, caveolae, and cholesterol levels. GPI-deficient cells were obtained by screening for resistance to the pore-forming toxin aerolysin, which uses this class of proteins as receptors. Despite the absence of GPI-anchored proteins, mutant cells still contained lipid rafts, indicating that GPI-anchored proteins are not crucial structural elements of these domains. Interestingly, the caveolae-specific membrane proteins, caveolin-1 and 2, were up-regulated in GPI-deficient cells, in contrast to flotillin-1 and GM1, which were expressed at normal levels. Additionally, the number of surface caveolae was increased. This effect was specific since recovery of GPI biosynthesis by gene recomplementation restored caveolin expression and the number of surface caveolae to wild type levels. The inverse correlation between the expression of GPI-anchored proteins and caveolin-1 was confirmed by the observation that overexpression of caveolin-1 in wild type cells led to a decrease in the expression of GPI-anchored proteins. In cells lacking caveolae, the absence of GPI-anchored proteins caused an increase in cholesterol levels, suggesting a possible role of GPI-anchored proteins in cholesterol homeostasis, which in some cells, such as Chinese hamster ovary cells, can be compensated by caveolin up-regulation.

Animals↗
PubMed2001

Receptor number and caveolar co-localization determine receptor coupling efficiency to adenylyl cyclase.

Recent evidence suggests that many signaling molecules localize in microdomains of the plasma membrane, particularly caveolae. In this study, overexpression of adenylyl cyclase was used as a functional probe of G protein-coupled receptor (GPCR) compartmentation. We found that three endogenous receptors in neonatal rat cardiomyocytes couple with different levels of efficiency to the activation of adenylyl cyclase type 6 (AC6), which localizes to caveolin-rich membrane fractions. Overexpression of AC6 enhanced the maximal cAMP response to beta(1)-adrenergic receptor (beta(1)AR)-selective activation 3.7-fold, to beta(2)AR-selective activation only 1.6-fold and to prostaglandin E(2) (PGE(2)) not at all. Therefore, the rank order of efficacy in coupling to AC6 is beta(1)AR > beta(2)AR > prostaglandin E(2) receptor (EP(2)R). beta(2)AR coupling efficiency was greater when we overexpressed the receptor or blocked its desensitization by expressing betaARKct, an inhibitor of G protein-coupled receptor kinase activation, but was not significantly greater when cells were treated with pertussis toxin. Assessment of receptor and AC expression indicated co-localization of AC5/6, beta(1)AR, and beta(2)AR, but not EP(2)R, in caveolin-rich membranes and caveolin-3 immunoprecipitates, likely explaining the observed activation of AC6 by betaAR subtypes but lack thereof by PGE(2). When cardiomyocytes were stimulated with a betaAR agonist, beta(2)AR were no longer found in caveolin-3 immunoprecipitates; an effect that was blocked by expression of betaARKct. Thus, agonist-induced translocation of beta(2)AR out of caveolae causes a sequestration of receptor from effector and likely contributes to the lower efficacy of beta(2)AR coupling to AC6 as compared with beta(1)AR, which do not similarly translocate. Therefore, spatial co-localization is a key determinant of efficiency of coupling by particular extracellular signals to activation of GPCR-linked effectors.

Adenylyl Cyclases↗
PubMed2005

Expression and localization of caveolins during postnatal development in rat heart: implication of thyroid hormone.

Caveolins modulate signaling pathways involved in cardiac development. Caveolin-1 exists in two isoforms: the beta-isoform derivates from an alternative translational start site that creates a protein truncated by 31 amino acids, mainly expressed in endothelial cells, whereas caveolin-3 is present in muscle cells. Our aim was to define caveolin distribution and expression during cardiac postnatal development using immunofluorescence and Western blotting. Caveolin-3 sarcolemmal labeling appeared as dotted lines from days 1 to 5 and as continuous lines after 14 days of age. Caveolin-3 expression, low at birth, increased (4-fold) to reach a maximum (P < 0.05) by day 5 and then decreased to stabilize in adults. Total caveolin-1 and its alpha-isoform were codistributed at birth in endothelial and smooth muscle cells; afterward, only the caveolin-1alpha labeling became limited to endothelium. Quantitative analysis indicated a similar temporal pattern of both total caveolin-1 and caveolin-1alpha expression, suggesting that caveolin-1alpha and -1beta are coregulated; the caveolin-1alpha levels increased fourfold by day 5 to reach a maximum by day 14 (P < 0.05). Tyrosine-14-caveolin-1 phosphorylation, low at birth, increased suddenly around day 14 (8-fold vs. day 1) and returning afterward to basal level. Because the T3/T4 level is maximal by day 14, caveolin-1 expression/phosphorylation profiles were analyzed in hypothyroid heart. The levels of caveolin-1alpha and consequently tyrosine-14-caveolin-1 phosphorylation, but not that of caveolin-3, decreased (50%) in hypothyroid 14-day-old rats. Our data demonstrate that, during postnatal cardiac growth, 1) caveolins are distinctly regulated, and 2) thyroid hormones are involved in caveolin-1alpha expression.

Adaptation, Physiological↗
PubMed2004

Subcellular immunolocalisation of fatty acid translocase (FAT)/CD36 in human type-1 and type-2 skeletal muscle fibres.

Limited information exists about the putative role and expression in human skeletal muscle cells of the 88-kDa integral membrane protein fatty acid translocase (FAT), highly homologous to the human leucocyte differentiation factor CD36. Therefore, we investigated in healthy male individuals the muscle (m. vastus lateralis) fibre type specific expression and subcellular localisation of FAT/CD36. For this purpose four different monoclonal antibodies raised against human and mouse FAT/CD36 were used. Acetone or methanol/acetone fixation were tested. Serial cryosections were cut at -20 degrees C, thaw-mounted on uncoated glass slides and air-dried before processing indirect immunofluorescence assays. Images were examined in a Nikon ER800 microscope, digitally captured, processed and analysed by LUCIA laboratory software. Three antibodies showed that FAT/CD36 was: (1) most abundantly expressed in capillary endothelium, (2) colocalised with caveolin-3, which indicates that FAT/CD36 is in the sarcolemma, or its close vicinity, and (3) abundantly expressed in (or in the close vicinity) of the sarcolemma and intracellular structures of type-1 muscle fibres, and much less abundantly in the sarcolemma of type-2 muscle fibres. One of the antibodies raised against mouse CD36 also detected myosin heavy chain 1, which makes it unsuitable in skeletal muscle research. The fixation (acetone or methanol/acetone) was found to be highly important for the result.

Adult↗
PubMed2002

Identification of differentially expressed genes in pulmonary adenocarcinoma by using cDNA array.

No clear patterns in molecular changes underlying the malignant processes in lung cancer of different histological types have been found so far. To identify critical genes in lung cancer progression we compared the expression profile of cancer related genes in 14 pulmonary adenocarcinoma patients with normal lung tissue by using the cDNA array technique. Principal component analyses (PCA) and permutation test were used to detect the differentially expressed genes. The expression profiles of 10 genes were confirmed by semi-quantitative real-time RT-PCR. In tumour samples, as compared to normal lung tissue, the up-regulated genes included such known tumour markers as CCNB1, PLK, tenascin, KRT8, KRT19 and TOP2A. The down-regulated genes included caveolin 1 and 2, and TIMP3. We also describe, for the first time, down-regulation of the interesting SOCS2 and 3, DOC2 and gravin. We show that silencing of SOCS2 is not caused by methylation of exon 1 of the gene. In conclusion, by using the cDNA array technique we were able to reveal marked differences in the gene expression level between normal lung and tumour tissue and find possible new tumour markers for pulmonary adenocarcinoma.

Adenocarcinoma↗
PubMed2005

Nur77 regulates lipolysis in skeletal muscle cells. Evidence for cross-talk between the beta-adrenergic and an orphan nuclear hormone receptor pathway.

Skeletal muscle is a major mass peripheral tissue that accounts for approximately 40% of total body weight and 50% of energy expenditure and is a primary site of glucose disposal and fatty acid oxidation. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. Excessive caloric intake is sensed by the brain and induces beta-adrenergic receptor (beta-AR)-mediated adaptive thermogenesis. Beta-AR null mice develop severe obesity on a high fat diet. However, the target gene(s), target tissues(s), and molecular mechanism involved remain obscure. We observed that 30-60 min of beta-AR agonist (isoprenaline) treatment of C2C12 skeletal muscle cells strikingly activated (>100-fold) the expression of the mRNA encoding the nuclear hormone receptor, Nur77. In contrast, the expression of other nuclear receptors that regulate lipid and carbohydrate metabolism was not induced. Stable transfection of Nur77-specific small interfering RNAs (siNur77) into skeletal muscle cells repressed endogenous Nur77 mRNA expression. Moreover, we observed attenuation of gene and protein expression associated with the regulation of energy expenditure and lipid homeostasis, for example AMP-activated protein kinase gamma3, UCP3, CD36, adiponectin receptor 2, GLUT4, and caveolin-3. Attenuation of Nur77 expression resulted in decreased lipolysis. Finally, in concordance with the cell culture model, injection and electrotransfer of siNur77 into mouse tibialis cranialis muscle resulted in the repression of UCP3 mRNA expression. This study demonstrates regulatory cross-talk between the nuclear hormone receptor and beta-AR signaling pathways. Moreover, it suggests Nur77 modulates the expression of genes that are key regulators of skeletal muscle lipid and energy homeostasis. In conclusion, we speculate that Nur77 agonists would stimulate lipolysis and increase energy expenditure in skeletal muscle and suggest selective activators of Nur77 may have therapeutic utility in the treatment of obesity.

Animals↗