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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, adipose triglyceride lipase (ATGL, also called desnutrin and calcium-independent phospholipase A2 [iPLA(2)] zeta) was isolated as a novel adipose-expressed triglyceride lipase which is downregulated in obesity and may contribute to obesity-associated metabolic disorders such as hyperlipidemia and insulin resistance. To clarify expression and regulation of this fat-derived lipase, ATGL mRNA was measured in 3T3-L1 adipocytes by quantitative real-time reverse transcription-polymerase chain reaction after treatment with isoproterenol, tumor necrosis factor (TNF) alpha, insulin, and growth hormone (GH) which have been shown to influence lipolysis and insulin sensitivity profoundly. Interestingly, treatment of adipocytes with 100 nM isoproterenol, 30 ng/ml TNF alpha, and 100 nM insulin for 16 h significantly decreased ATGL mRNA to 74%, 17%, and 49% of control levels, respectively. GH did not influence ATGL synthesis. The effect of isoproterenol, TNFalpha, and insulin on ATGL expression was time- and dose-dependent. Similarly, HSL mRNA was downregulated by the three hormones. Furthermore, signaling studies suggested that activation of Gs-protein-coupled pathways by forskolin and cholera toxin is sufficient to significantly downregulate ATGL mRNA. Moreover, p44/42 mitogen-activated protein kinase appears to partly mediate the negative effect of insulin but not TNFalpha on ATGL. Taken together, downregulation of ATGL by isoproterenol, TNFalpha, and insulin might contribute to dysregulated expression and function of this lipase in obesity, hyperlipidemia, and insulin resistance.
Mol Cell Endocrinol 2005 Aug 30
PMID:Isoproterenol, TNFalpha, and insulin downregulate adipose triglyceride lipase in 3T3-L1 adipocytes. 1600 85

Mammalian hibernation requires an extensive reorganization of metabolism that typically includes a greater than 95% reduction in metabolic rate, selective inhibition of many ATP-consuming metabolic activities and a change in fuel use to a primary dependence on the oxidation of lipid reserves. We investigated whether the AMP-activated protein kinase (AMPK) could play a regulatory role in this reorganization. AMPK activity and the phosphorylation state of multiple downstream targets were assessed in five organs of thirteen-lined ground squirrels (Spermophilus tridecemlineatus) comparing euthermic animals with squirrels in deep torpor. AMPK activity was increased 3-fold in white adipose tissue from hibernating ground squirrels compared with euthermic controls, but activation was not seen in liver, skeletal muscle, brown adipose tissue or brain. Immunoblotting with phospho-specific antibodies revealed an increase in phosphorylation of eukaryotic elongation factor-2 at the inactivating Thr56 site in white adipose tissue, liver and brain of hibernators, but not in other tissues. Acetyl-CoA carboxylase phosphorylation at the inactivating Ser79 site was markedly increased in brown adipose tissue from hibernators, but no change was seen in white adipose tissue. No change was seen in the level of phosphorylation of the Ser565 AMPK site of hormone-sensitive lipase in adipose tissues of hibernating animals. In conclusion, AMPK does not appear to participate in the metabolic re-organization and/or the metabolic rate depression that occurs during ground squirrel hibernation.
Comp Biochem Physiol B Biochem Mol Biol 2005 Dec
PMID:Evaluation of the role of AMP-activated protein kinase and its downstream targets in mammalian hibernation. 1620 35

The three-dimensional structure of a complex between the N-terminal domain of the quorum sensing protein SdiA of Escherichia coli and a candidate autoinducer N-octanoyl-L-homoserine lactone (C8-HSL) has been calculated in solution from NMR data. The SdiA-HSL system shows the "folding switch" behavior that has been seen for quorum-sensing factors produced by other bacterial species. In the presence of C8-HSL, a significant proportion of the SdiA protein is produced in a folded, soluble form in an E.coli expression system, whereas in the absence of acyl homoserine lactones, the protein is expressed into insoluble inclusion bodies. In the three-dimensional structure, the autoinducer molecule is sequestered in a deep pocket in the hydrophobic core, forming an integral part of the core packing of the folded SdiA. The NMR spectra of the complex show that the bound C8-HSL is conformationally heterogeneous, either due to motion within the pocket or to heterogeneity of the bound structure. The C8-HSL conformation is defined by NOEs to the protein only at the terminal methyl group of the octanoyl chain. Unlike other well-studied bacterial quorum sensing systems such as LuxR of Vibrio fischeri and TraR of Agrobacterium tumefaciens, there is no endogenous autoinducer for SdiA in E.coli: the E.coli genome does not contain a gene analogous to the LuxI and TraI autoinducer synthetases. We show that two other homoserine lactone derivatives are also capable of acting as a folding-switch autoinducers for SdiA. The observed structural heterogeneity of the bound C8-HSL in the complex, together with the variety of autoinducer-type molecules that can apparently act as folding switches in this system, are consistent with the postulated biological function of the SdiA protein as a detector of the presence of other species of bacteria.
J Mol Biol 2006 Jan 13
PMID:Structure of the Escherichia coli quorum sensing protein SdiA: activation of the folding switch by acyl homoserine lactones. 1630 57

The opportunistic pathogen Pseudomonas aeruginosa has two acyl-homoserine lactone (acyl-HSL) signalling systems, LasR-I and RhlR-I. LasI catalyses the synthesis of N-3-oxododecanoyl homoserine lactone (3OC12) and LasR is a transcription factor that requires 3OC12 as a ligand. RhlI catalyses the synthesis of N-butanoyl homoserine lactone (C4) and RhlR is a transcription factor that responds to C4. LasR and RhlR control the transcription of hundreds of P. aeruginosa genes. There is a third P. aeruginosa LasR-RhlR homologue encoded by qscR for which there is no cognate acyl-HSL synthase gene. To test the hypothesis that QscR functions by direct control of specific promoters in an acyl-HSL-dependent manner we purified QscR and characterized QscR activity in vitro. We also studied QscR activity in recombinant Escherichia coli. QscR binds to promoters that have elements similar in sequence to those found in LasR- or RhlR-dependent promoters but QscR does not bind to the LasR- or RhlR-specific promoters we examined. QscR binding to DNA requires 3OC12, but QscR exhibits a relaxed acyl-HSL specificity compared with the 3OC12-cognate signal receptor LasR. Our results support the hypothesis that there is a specific QscR-dependent regulon. We show that QscR controls genes in this regulon directly and that regulation is dependent on an acyl-HSL produced by LasI. Because of its relaxed signal specificity QscR may also respond to acyl-HSLs made by other bacteria in mixed bacterial communities.
Mol Microbiol 2006 Jan
PMID:Activity of purified QscR, a Pseudomonas aeruginosa orphan quorum-sensing transcription factor. 1639 Apr 53

The Pseudomonas aeruginosa quorum-sensing (QS) systems, Las and Rhl, control the production of several virulence factors and other proteins, which are important to sustain adverse conditions. A comparative transcriptome analysis of a rpoS (-) and a rpoS(-)hfq( -) strain indicated that the Sm-like RNA-binding protein Hfq affects approximately 5% of the P. aeruginosa O1 transcripts. Among these transcripts 72 were identified to be QS regulated. Expression studies revealed that Hfq does not control the master regulators of the Las system, LasR and LasI. Upon entry into stationary phase, Hfq exerted a moderate stimulatory effect on translation of the rhlR gene and on the qscR gene, encoding a LasR/RhlR homologue. However, Hfq considerably stimulated translation of the rhlI gene, encoding the synthetase of the autoinducer N-Butyryl-homoserine lactone (C4-HSL). Correspondingly, the C4-HSL levels were reduced in a hfq(-) strain. To elucidate the stimulatory effect of Hfq on rhlI expression we asked whether Hfq affects the stability of the regulatory RNAs RsmY and RsmZ, which have been implicated in sequestration of the translational repressor RsmA, which in turn is known to negatively regulate RhlI synthesis. We demonstrate that Hfq binds to and stabilizes the regulatory RNA RsmY, which is further shown to bind to the regulatory protein RsmA. A model for the Hfq regulatory network is presented, wherein an alleviation of the negative effect of RsmA accounts for the observed stimulation of rhlI expression by Hfq. The model is corroborated by the observation that a rsmY(-) mutant mimics the hfq(-) phenotype with regard to rhlI expression.
Mol Microbiol 2006 Mar
PMID:Hfq-dependent alterations of the transcriptome profile and effects on quorum sensing in Pseudomonas aeruginosa. 1646 94

Two N-acyl-homoserine lactone (acyl-HSL) synthase genes, lasI from Pseudomonas aeruginosa and yenI from Yersinia enterocolitica, were introduced into tobacco, individually and in combination. Liquid chromatograph-tandem mass spectrometry and thin-layer chromatography confirmed products of lasI and yenI activity in single and cotransformants. Cotransformants expressing plastid-localized LasI and YenI synthases produced the major acyl-HSLs for each synthase in all tissues tested. Total acyl-HSL signals accumulated in leaf tissue up to 3 pmol/mg of fresh weight, half as much in stem tissue, and approximately 10-fold less in root tissues. Acyl-HSLs were present in aqueous leaf washes from greenhouse-grown transgenic plants. Transgenic lines grown for 14 days under axenic conditions produced detectable levels of acyl-HSLs in root exudates. Ethyl acetate extractions of rhizosphere and nonrhizosphere soil from transgenically grown plants contained active acyl-HSLs, whereas plant-free soil or rhizosphere and nonrhizosphere soil from wild-type plants lacked detectable amounts of acyl-HSLs. This work shows that bioactive acyl-HSLs are exuded from leaves and roots and accumulate in the phytosphere of plants engineered to produce acyl-HSLs. These data further suggest that plants that are bioengineered to synthesize acyl-HSLs can foster beneficial plant-bacteria communications or deter deleterious interactions. Therefore, it is feasible to use bioengineered plants to supplement soils with specific acyl-HSLs to modulate bacterial phenotypes and plant-associated bacterial community structures.
Mol Plant Microbe Interact 2006 Mar
PMID:Long- and short-chain plant-produced bacterial N-acyl-homoserine lactones become components of phyllosphere, rhizosphere, and soil. 1657 Jun 53

Quorum sensing, the population density-dependent regulation mediated by N-acylhomoserine lactones (AHSL), is essential for the control of virulence in the plant pathogen Erwinia carotovora ssp. carotovora (Ecc). In Erwinia carotovora ssp. the AHSL signal with an acyl chain of either 6 or 8 carbons is generated by an AHSL synthase, the expI gene product. This work demonstrates that the AHSL receptor, ExpR1, of Ecc strain SCC3193 has strict specificity for the cognate AHSL 3-oxo-C8-HSL. We have also identified a second AHSL receptor (ExpR2) and demonstrate a novel quorum sensing mechanism, where ExpR2 acts synergistically with the previously described ExpR1 to repress virulence gene expression in Ecc. We show that this repression is released by addition of AHSLs and appears to be largely mediated via the negative regulator RsmA. Additionally we show that ExpR2 has the novel property to sense AHSLs with different acyl chain lengths. The expI expR1 double mutant is able to act in response to a number of different AHSLs, while the expI expR2 double mutant can only respond to the cognate signal of Ecc strain SCC3193. These results suggest that Ecc is able to react both to the cognate AHSL signal and the signals produced by other bacterial species.
Mol Microbiol 2006 Jun
PMID:Cooperation of two distinct ExpR regulators controls quorum sensing specificity and virulence in the plant pathogen Erwinia carotovora. 1679 82

The production of several virulence factors by Pseudomonas aeruginosa is regulated through the hierarchical cell-density dependent quorum sensing (QS) systems las and rhl. A third component of the QS hierarchy, the Pseudomonas quinolone signal PQS, also controls the expression of several genes. We previously described P. aeruginosa PtxR as a transcriptional activator of the exotoxin A gene toxA. Here, we provide evidence that PtxR regulates the production of other virulence factors. Mutation of ptxR in PAO1 increased pyocyanin production. This increase was reduced in the presence of a ptxR plasmid. Throughout the growth cycle, PtxR reduced the expression of the pyocyanin operon phzA1-G1 but not phzA2-G2. As pyocyanin production is stringently controlled by QS, we examined the effect of PtxR on QS-related genes in PAO1. PtxR also reduced the expression of the PQS synthesis operon pqsABCDE. ptxR mutation increased the expression of the rhamnolipid synthesis gene rhlA but decreased lasB expression. The expression of the RhlI synthase gene rhlI and the production of the C(4)-HSL autoinducer were increased in the ptxR mutant, while the expression of the LasI synthase gene lasI and the production of 3OC(12)-HSL were reduced. These results suggest that PtxR negatively regulates the expression of the rhamnolipid and pyocyanin genes through rhlI and the pqsABCDE operon while it positively regulates the expression of lasB through lasI.
Mol Microbiol 2006 Aug
PMID:PtxR modulates the expression of QS-controlled virulence factors in the Pseudomonas aeruginosa strain PAO1. 1680 94

Upstream transcription factor 1 (USF1) regulates the expression of many genes involved in lipid and glucose metabolism, among them genes regulating lipolysis. USF1 specifically regulates the expression of the hormone-sensitive lipase gene (HSL) in adipocytes and the hepatic lipase gene (LIPC) in the liver, which was found to be involved in liver fat accumulation. The usf1s1 C > T and usf1s2 G > A single-nucleotide polymorphisms (SNPs) in USF1 are associated with increased in vitro catecholamine-induced lipolysis in adipocytes. We investigated first whether SNPs in USF1 affect the lipolysis-suppressing action of insulin in vivo, and second, whether they interact with the -60C > G SNP in HSL on lipolysis and the -514C > T SNP in LIPC on liver fat. The usf1s1 C > T and usf1s2 G > A SNPs, together with the SNPs in HSL and LIPC, were determined in 407 Caucasians. Lipolysis was estimated as a change in free fatty acid (FFA) levels from baseline to 2 h of a 75-g oral glucose tolerance test (OGTT). Fifty-four subjects had data from a euglycemic hyperinsulinemic clamp with calculation of antilipolytic insulin sensitivity. Subjects carrying the minor alleles (T of usf1s1 and A of usf1s2) had lower 2 h FFA (p = 0.01) and a larger decrease in FFA concentrations during the OGTT (p = 0.02). Antilipolytic insulin sensitivity was higher in these individuals (p = 0.03). No interaction of the usf1s1 C > T and usf1s2 G > A SNPs with the -60C > G SNP in HSL on antilipolytic insulin sensitivity was detected. Liver fat, measured by (1)H magnetic resonance spectroscopy, was elevated only in subjects who were both homozygous for the major alleles of usf1s1 and usf1s2 and carriers of the T allele of the -514C > T SNP in LIPC (p = 0.01). In conclusion, subjects carrying the T allele of SNP usf1s1 and the A allele of SNP usf1s2 have a higher antilipolytic insulin sensitivity. Moreover, both SNPs may interact with the -514C > T SNP in LIPC to determine liver fat.
J Mol Med (Berl) 2007 Jan
PMID:Upstream transcription factor 1 gene polymorphisms are associated with high antilipolytic insulin sensitivity and show gene-gene interactions. 1701 91

Pseudomonas aeruginosa is an important cause of nosocomial infections and is frequently present in the airways of cystic fibrosis patients. Quorum sensing mediates P. aeruginosa's virulence and biofilm formation through density-dependent interbacterial signaling with autoinducers. N-3-oxododecanoyl homoserine lactone (3OC12-HSL) is the major autoinducer in P. aeruginosa. We have previously shown that human airway epithelia and paraoxonases (PONs) degrade 3OC12-HSL. This study investigated the role of PON1, PON2, and PON3 in airway epithelial cell inactivation of 3OC12-HSL. All three PONs were present in murine tracheal epithelial cells, with PON2 and PON3 expressed at the highest levels. Lysates of tracheal epithelial cells from PON2, but not PON1 or PON3, knockout mice had impaired 3OC12-HSL inactivation compared with wild-type mice. In contrast, PON1-, PON2-, or PON3-targeted deletions did not affect 3OC12-HSL degradation by intact epithelia. Overexpression of PON2 enhanced 3OC12-HSL degradation by human airway epithelial cell lysates but not by intact epithelia. Finally, using a quorum-sensing reporter strain of P. aeruginosa, we found that quorum sensing was enhanced in PON2-deficient airway epithelia. In summary, these results show that loss of PON2 impairs 3OC12-HSL degradation by airway epithelial cells and suggests that diffusion of 3OC12-HSL into the airway cells can be the rate-limiting step for degradation of the molecule.
Am J Physiol Lung Cell Mol Physiol 2007 Apr
PMID:Paraoxonase-2 deficiency enhances Pseudomonas aeruginosa quorum sensing in murine tracheal epithelia. 1712 53


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