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- Chernogubova, Ekaterina, 1967-
(författare)
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Adrenergic stimulation of glucose uptake in brown adipocytes
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this study was to investigate adrenergically stimulated glucose uptake in brown adipose tissue (BAT) with the focus on receptor subtypes and intracellular signalling pathways. As a model system, we used primary cultured brown adipocytes.Adrenergic stimulation of glucose uptake occurs via β3-AR in wild type cells and β1-/α1-ARs in β3-KO cells, includes activation of adenylyl cyclase and cAMP formation, activation of PKA, PI3K, PKC and AMPK (Paper I, II, III). Interestingly, UCP1 activity is not required for the AMPK function in brown adipocytes (Paper III). Long-term adrenergic stimulation of glucose uptake induces an increase in GLUT1 mRNA and protein levels stimulating GLUT1 translocation to the plasma membrane (Paper IV).
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| 2. |
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| 3. |
- Chernogubova, Ekaterina, et al.
(författare)
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Common and Low-Frequency Genetic Variants in the PCSK9 Locus Influence Circulating PCSK9 Levels
- 2012
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 32:6, s. 1526-1534
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Tidskriftsartikel (refereegranskat)abstract
- Objective- Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that influences plasma low-density lipoprotein concentration and susceptibility to coronary heart disease. Circulating PCSK9 levels show considerable interindividual differences, but the factors responsible for this variation are largely unknown. Methods and Results- We analyzed circulating PCSK9 levels in 4 cohorts of healthy, middle-aged Swedes (n=5722) and found that PCSK9 levels varied over approximate to 50-fold range, showed a positive relationship with plasma low-density lipoprotein-cholesterol concentration, and were associated with plasma triglyceride, fibrinogen, insulin, and glucose concentrations. A genome-wide association study conducted in 2 cohorts (n=1215) failed to uncover common genetic variants robustly associated with variation in circulating PCSK9 level. As expected, the minor allele of the PCSK9 R46L variant was in all cohorts associated with reduced PCSK9 levels and decreased plasma low-density lipoprotein-cholesterol concentrations, but no relationship was observed with the plasma triglyceride concentration. Further mapping of the PCSK9 locus revealed a common polymorphism (rs2479415, minor allele frequency 43.9%), located approximate to 6 kb upstream from PCSK9, which is independently associated with increased circulating PCSK9 levels. Conclusion- Common and low-frequency genetic variants in the PCSK9 locus influence the pronounced interindividual variation in circulating PCSK9 levels in healthy, middle-aged white (predominantly Swedish) subjects.
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| 6. |
- Dallner, Olof S., et al.
(författare)
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β3-adrenergic receptors stimulate glucose uptake in brown adipocytes by two mechanisms independently of GLUT4 translocation
- 2006
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 147:12, s. 5730-5739
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Tidskriftsartikel (refereegranskat)abstract
- To identify the mechanisms whereby norepinephrine induces glucose uptake in brown adipose tissue, we used mouse brown adipocytes in culture. Proliferating brown adipocytes had high levels of glucose transporter (GLUT) 1 mRNA and low levels of GLUT4 mRNA. The ratio of GLUT4/GLUT1 mRNA expression increased during differentiation, and mature brown adipocytes had high levels of GLUT4 mRNA. The endogenous adrenergic neurotransmitter norepinephrine induced a potent increase in GLUT1 mRNA and a decrease of GLUT4 mRNA in mature brown adipocytes. The norepinephrine effect was mimicked by isoprenaline and CL 316243 and was thus mediated by beta(3)-adrenergic receptors. The cAMP analog 8-bromoadenosine-cAMP partly mimicked the response on GLUT1 mRNA increase and fully mimicked the GLUT4 mRNA decrease. We found no involvement of alpha(1) or alpha(2)-adrenergic receptors on GLUT1 or GLUT4 mRNA transcription. Norepinephrine treatment led to a large increase of GLUT1 protein amount in brown adipocytes as visualized with immunocytochemical staining and subcellular fractionation. A large part of the newly synthesized GLUT1 was found in the plasma membrane (PM). The potent transcriptional inhibitor actinomycin D fully abolished this increase of GLUT1 protein at all time points examined. Norepinephrine treatment shifted GLUT4 from the PM to an intracellular vesicular compartment. Norepinephrine increased 2-deoxy-D-glucose uptake 2-fold at an early time point ( 1 h) and 4-fold at later time point ( 5 h). Addition of actinomycin D did not block the early phase but blocked a large part of the later phase of 2-deoxy-D-glucose uptake. These results imply that adrenergic stimulation through beta(3)-adrenergic receptors induces glucose uptake in brown adipocytes via two mechanisms: 1) a mechanism not dependent on GLUT1 and GLUT4 translocation, 2) a mechanism that is dependent on de novo synthesis of GLUT1 protein and increase of GLUT1 protein at the PM.
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| 7. |
- Folkersen, Lasse, et al.
(författare)
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Association of genetic risk variants with expression of proximal genes identifies novel susceptibility genes for cardiovascular disease
- 2010
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Ingår i: Circulation. - 1942-325X .- 1942-3268. ; 3:4, s. 365-373
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Population-based genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with cardiovascular disease or its risk factors. Genes in close proximity to these risk-SNPs are often thought to be pathogenetically important based on their location alone. However, the actual connections between SNPs and disease mechanisms remain largely unknown. METHODS AND RESULTS: To identify novel susceptibility genes, we investigated how 166 SNPs previously found to be associated with increased cardiovascular risk and/or predisposing metabolic traits relate to the expression of nearby genes. Gene expression in 577 samples of aorta, liver, mammary artery, and carotid atherosclerotic plaque was measured using expression arrays. For 47 SNPs, the expression levels of proximal genes (located within 200 kb) were affected (P<0.005). More than 20 of these genes had not previously been identified as candidate genes for cardiovascular or related metabolic traits. SNP-associated gene effects were tissue-specific and the tissue specificity was phenotype-dependent. CONCLUSIONS: This study demonstrates several instances of association between risk-SNPs and genes immediately adjacent to them. It also demonstrates instances in which the associated gene is not the immediately proximal and obvious candidate gene for disease. This shows the necessity of careful studies of genetic marker data as a first step toward application of genome-wide association studies findings in a clinical setting.
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| 9. |
- Li, Daniel Y., et al.
(författare)
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H19 Induces Abdominal Aortic Aneurysm Development and Progression
- 2018
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Ingår i: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0009-7322 .- 1524-4539. ; 138:15, s. 1551-1568
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Tidskriftsartikel (refereegranskat)abstract
- Background: Long noncoding RNAs have emerged as critical molecular regulators in various biological processes and diseases. Here we sought to identify and functionally characterize long noncoding RNAs as potential mediators in abdominal aortic aneurysm development. Methods: We profiled RNA transcript expression in 2 murine abdominal aortic aneurysm models, Angiotensin II (ANGII) infusion in apolipoprotein E-deficient (ApoE(-/-)) mice (n=8) and porcine pancreatic elastase instillation in C57BL/6 wild-type mice (n=12). The long noncoding RNA H19 was identified as 1 of the most highly upregulated transcripts in both mouse aneurysm models compared with sham-operated controls. This was confirmed by quantitative reverse transcription-polymerase chain reaction and in situ hybridization. Results: Experimental knock-down of H19, utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) in vivo, significantly limited aneurysm growth in both models. Upregulated H19 correlated with smooth muscle cell (SMC) content and SMC apoptosis in progressing aneurysms. Importantly, a similar pattern could be observed in human abdominal aortic aneurysm tissue samples, and in a novel preclinical LDLR-/- (low-density lipoprotein receptor) Yucatan mini-pig aneurysm model. In vitro knock-down of H19 markedly decreased apoptotic rates of cultured human aortic SMCs, whereas overexpression of H19 had the opposite effect. Notably, H19-dependent apoptosis mechanisms in SMCs appeared to be independent of miR-675, which is embedded in the first exon of the H19 gene. A customized transcription factor array identified hypoxia-inducible factor 1 as the main downstream effector. Increased SMC apoptosis was associated with cytoplasmic interaction between H19 and hypoxia-inducible factor 1 and sequential p53 stabilization. Additionally, H19 induced transcription of hypoxia-inducible factor 1 via recruiting the transcription factor specificity protein 1 to the promoter region. Conclusions: The long noncoding RNA H19 is a novel regulator of SMC survival in abdominal aortic aneurysm development and progression. Inhibition of H19 expression might serve as a novel molecular therapeutic target for aortic aneurysm disease.
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| 10. |
- Mattsson, Charlotte L., et al.
(författare)
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β₁-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β₃-adrenergic receptor-knockout mice via nonshivering thermogenesis
- 2011
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 301:6, s. E1108-E1118
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Tidskriftsartikel (refereegranskat)abstract
- With the finding that brown adipose tissue is present and negatively correlated to obesity in adult man, finding the mechanism(s) of how to activate brown adipose tissue in humans could be important in combating obesity, type 2 diabetes, and their complications. In mice, the main regulator of nonshivering thermogenesis in brown adipose tissue is norepinephrine acting predominantly via β(3)-adrenergic receptors. However, vast majorities of β(3)-adrenergic agonists have so far not been able to stimulate human β(3)-adrenergic receptors or brown adipose tissue activity, and it was postulated that human brown adipose tissue could be regulated instead by β(1)-adrenergic receptors. Therefore, we have investigated the signaling pathways, specifically pathways to nonshivering thermogenesis, in mice lacking β(3)-adrenergic receptors. Wild-type and β(3)-knockout mice were either exposed to acute cold (up to 12 h) or acclimated for 7 wk to cold, and parameters related to metabolism and brown adipose tissue function were investigated. β(3)-knockout mice were able to survive both acute and prolonged cold exposure due to activation of β(1)-adrenergic receptors. Thus, in the absence of β(3)-adrenergic receptors, β(1)-adrenergic receptors are effectively able to signal via cAMP to elicit cAMP-mediated responses and to recruit and activate brown adipose tissue. In addition, we found that in human multipotent adipose-derived stem cells differentiated into functional brown adipocytes, activation of either β(1)-adrenergic receptors or β(3)-adrenergic receptors was able to increase UCP1 mRNA and protein levels. Thus, in humans, β(1)-adrenergic receptors could play an important role in regulating nonshivering thermogenesis.
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