| 1. |
- Martrat, Griselda, et al.
(författare)
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Exploring the link between MORF4L1 and risk of breast cancer
- 2011
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 13:2
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to g-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, P-trend = 0.45 and 0.05, P-2df = 0.51 and 0.14, respectively; and rs10519219, P-trend = 0.92 and 0.72, P-2df = 0.76 and 0.07, respectively. Conclusions: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.
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| 2. |
- deSchoolmeester, J., et al.
(författare)
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Differences between men and women in the regulation of adipose 11 beta-HSD1 and in its association with adiposity and insulin resistance
- 2013
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Ingår i: Diabetes, obesity and metabolism. - : Wiley-Blackwell. - 1462-8902 .- 1463-1326. ; 15:11, s. 1056-1060
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Tidskriftsartikel (refereegranskat)abstract
- This study explored sex differences in 11-hydroxysteroid dehydrogenase type 1 (11-HSD1) activity and gene expression in isolated adipocytes and adipose tissue (AT), obtained via subcutaneous biopsies from non-diabetic subjects [58 M, 64 F; age 48.3 +/- 15.3years, body mass index (BMI) 27.2 +/- 3.9kg/m(2)]. Relationships with adiposity and insulin resistance (IR) were addressed. Males exhibited higher 11-HSD1 activity in adipocytes than females, but there was no such difference for AT. In both men and women, adipocyte 11-HSD1 activity correlated positively with BMI, waist circumference, % body fat, adipocyte size and with serum glucose, triglycerides and low-density lipoprotein:high-density lipoprotein (LDL:HDL) ratio. Positive correlations with insulin, HOMA-IR and haemoglobin A1c (HbA1c) and a negative correlation with HDL-cholesterol were significant only in males. Conversely, 11-HSD1 activity in AT correlated with several markers of IR and adiposity in females but not in males, but the opposite pattern was found with respect to 11-HSD1 mRNA expression. This study suggests that there are sex differences in 11-HSD1 regulation and in its associations with markers of obesity and IR.
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| 3. |
- Fuhrmann, A., et al.
(författare)
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Molecular mechanisms underlying the effects of cyclosporin A and sirolimus on glucose and lipid metabolism in liver, skeletal muscle and adipose tissue in an in vivo rat model
- 2014
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Ingår i: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1356-1839. ; 88:2, s. 216-228
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Tidskriftsartikel (refereegranskat)abstract
- Cyclosporin A (CsA) and sirolimus (SRL) are immunosuppressive agents (IAs) associated with dyslipidemia, insulin resistance and new onset diabetes after transplantation (NODAT). However, the molecular mechanisms involved are not fully understood. We investigated the effects of six-week treatment of either CsA or SRL on glucose and lipid metabolism in Wistar rats. The results show that, compared with vehicle-treated rats, SRL-treated rats were significantly lighter starting at week 5. CsA or SRL caused glucose intolerance, increased storage of lipids in the liver and skeletal muscle, and decreased the insulin-stimulated glucose uptake in isolated adipocytes. Furthermore, these agents significantly decreased genes involved in insulin action and glucose uptake, such as, IRS-1, Glut4 and Glut1, and increased genes and/or proteins involved in hepatic lipogenesis and gluconeogenesis, while decreasing them in adipose tissue. After either treatment PGC1 alpha gene expression was down regulated in skeletal muscle, an important player in fatty acid oxidation. Moreover, there was an increase in IL-6 gene expression in adipose tissue in the SRL-treated rats, suggesting stimulation of lipolysis. The results of the present study suggest that CsA and SRL lead to metabolic alterations in liver, muscle and adipose tissue, which may contribute to the development of dyslipidemia and insulin resistance associated with immunosuppressive therapy. (C) 2014 Elsevier Inc. All rights reserved.
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| 4. |
- Lopes, P., et al.
(författare)
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Effects of Cyclosporine and Sirolimus on Insulin-Stimulated Glucose Transport and Glucose Tolerance in a Rat Model
- 2013
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Ingår i: Transplantation Proceedings. - : Elsevier BV. - 0041-1345 .- 1873-2623. ; 45:3, s. 1142-1148
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Tidskriftsartikel (refereegranskat)abstract
- Cyclosporine (CsA) and sirolimus (SRL) have been associated with undesirable side effects, including posttransplantation diabetes and hyperlipidemia, but the molecular mechanisms underlying these effects remain to be elucidated. Animal studies focusing on clinically relevant doses are advised. This study sought to compare the metabolic effects on isolated rat adipocytes treated with either CsA or SRL ex vivo and after long-term in vivo treatment in Wistar rats. We assessed the ex vivo effects of CsA (0.5–30 μmol/L) and SRL (1–250 μmol/L) on insulin-stimulated 14C-glucose uptake in epididymal adipocytes (n = 6–9). In parallel, rats (n = 12) were treated with either vehicle, CsA (5 mg/kg/d) or SRL (1 mg/kg/d) for either 3 or 9 weeks. At the end of the treatment, glucose tolerance test (GTT) and insulin-stimulated 14C-glucose uptake as well as biochemical parameters were analyzed. A significant reduction in the insulin-stimulated glucose uptake over basal was observed among isolated adipocytes, whether exposed ex vivo or in vivo to CsA or SRL treatment. Furthermore, the SRL group showed significantly lighter fat pads and smaller adipocytes at 3 weeks with a smaller gain in body weight throughout the study compared with either the vehicle or CsA cohorts. Glucose intolerance was observed after a GTT, at the end of the treatment with either drug. Additionally, at 9 weeks serum triglycerides were increased by CsA compared with vehicle or SRL treatment. Interestingly, although SRL-treated animals presented higher fed and fasted insulin levels compared with either group, suggesting insulin resistance, the CsA group presented lower fed and fasted insulin values, suggesting a defect in insulin secretion at 9 weeks. These results suggested that either ex vivo treatment of fat cells or in vivo treatment of rats with CsA or SRL impaired insulin-stimulated glucose uptake by adipocytes. Both drugs caused glucose intolerance, which altogether could be responsible for the development of posttransplantation diabetes. The introduction of calcineurin inhibitors, like cyclosporine (CsA), has been important to save lives and improve the safety of organ transplantations. However, the use of these drugs is followed by the emergence of a number of side effects that impact the patient's quality of life. One of the most important is new-onset diabetes mellitus after transplantation (NODAT),1, 2 and 3 which is usually associated with an increased risk of cardiovascular diseases and consequently decreased patient survival.3, 4 and 5 CsA, a peptide of fungal origin, CsA, forms a complex with cyclophilins, which then inhibits calcineurin, preventing the movement of transcription factors into the nucleus, thus blocking interleukin (IL)-2 production and, consequently, proliferation and differentiation of T cells.6 and 7 Studies on purified islets and insulin-producing beta cells have proposed various diabetogenic actions of CsA. Therefore, CsA decreases insulin content of the beta cell, reversibly inhibiting insulin gene transcription and ultimately insulin secretion,8 although the mechanisms that lead to these effects are not well understood.
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| 5. |
- Pereira, Maria J, 1981-, et al.
(författare)
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FKBP5 expression in human adipose tissue increases following dexamethasone exposure and is associated with insulin resistance
- 2014
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Ingår i: Metabolism: Clinical and Experimental. - : Elsevier BV. - 0026-0495 .- 1532-8600. ; 63:9, s. 1198-1208
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Tidskriftsartikel (refereegranskat)abstract
- Objective To study effects of dexamethasone on gene expression in human adipose tissue aiming to identify potential novel mechanisms for glucocorticoid-induced insulin resistance. Materials/methods Subcutaneous and omental adipose tissue, obtained from non-diabetic donors (10 M/15 F; age: 28-60 years; BMI: 20.7-30.6 kg/m2), was incubated with or without dexamethasone (0.003-3 μmol/L) for 24 h. Gene expression was assessed by microarray and real time-PCR and protein expression by immunoblotting. Results FKBP5 (FK506-binding protein 5) and CNR1 (cannabinoid receptor 1) were the most responsive genes to dexamethasone in both subcutaneous and omental adipose tissue (~ 7-fold). Dexamethasone increased FKBP5 gene and protein expression in a dose-dependent manner in both depots. The gene product, FKBP51 protein, was 10-fold higher in the omental than in the subcutaneous depot, whereas the mRNA levels were similar. Higher FKBP5 gene expression in omental adipose tissue was associated with reduced insulin effects on glucose uptake in both depots. Furthermore, FKBP5 gene expression in subcutaneous adipose tissue was positively correlated with serum insulin, HOMA-IR and subcutaneous adipocyte diameter and negatively with plasma HDL-cholesterol. FKBP5 SNPs were found to be associated with type 2 diabetes and diabetes-related phenotypes in large population-based samples. Conclusions Dexamethasone exposure promotes expression of FKBP5 in adipose tissue, a gene that may be implicated in glucocorticoid-induced insulin resistance. © 2014 Elsevier Inc.
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| 6. |
- Yi, Chuixiang, et al.
(författare)
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Climate control of terrestrial carbon exchange across biomes and continents
- 2010
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Ingår i: Environmental Research Letters. - : IOP Publishing. - 1748-9326. ; 5:3
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the relationships between climate and carbon exchange by terrestrial ecosystems is critical to predict future levels of atmospheric carbon dioxide because of the potential accelerating effects of positive climate-carbon cycle feedbacks. However, directly observed relationships between climate and terrestrial CO2 exchange with the atmosphere across biomes and continents are lacking. Here we present data describing the relationships between net ecosystem exchange of carbon (NEE) and climate factors as measured using the eddy covariance method at 125 unique sites in various ecosystems over six continents with a total of 559 site-years. We find that NEE observed at eddy covariance sites is (1) a strong function of mean annual temperature at mid-and high-latitudes, (2) a strong function of dryness at mid-and low-latitudes, and (3) a function of both temperature and dryness around the mid-latitudinal belt (45 degrees N). The sensitivity of NEE to mean annual temperature breaks down at similar to 16 degrees C (a threshold value of mean annual temperature), above which no further increase of CO2 uptake with temperature was observed and dryness influence overrules temperature influence.
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| 7. |
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| 9. |
- Pereira, Maria J, et al.
(författare)
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mTOR inhibition with rapamycin causes impaired insulin signalling and glucose uptake in human subcutaneous and omental adipocytes
- 2012
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Ingår i: Molecular and Cellular Endocrinology. - : Elsevier BV. - 0303-7207 .- 1872-8057. ; 355:1, s. 96-105
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Tidskriftsartikel (refereegranskat)abstract
- Rapamycin is an immunosuppressive agent used after organ transplantation, but its molecular effects on glucose metabolism needs further evaluation. We explored rapamycin effects on glucose uptake and insulin signalling proteins in adipocytes obtained via subcutaneous (n=62) and omental (n=10) fat biopsies in human donors. At therapeutic concentration (0.01 μM) rapamycin reduced basal and insulin-stimulated glucose uptake by 20-30%, after short-term (15 min) or long-term (20 h) culture of subcutaneous (n=23 and n=10) and omental adipocytes (n=6 and n=7). Rapamycin reduced PKB Ser473 and AS160 Thr642 phosphorylation, and IRS2 protein levels in subcutaneous adipocytes. Additionally, it reduced mTOR-raptor, mTOR-rictor and mTOR-Sin1 interactions, suggesting decreased mTORC1 and mTORC2 formation. Rapamycin also reduced IR Tyr1146 and IRS1 Ser307/Ser616/Ser636 phosphorylation, whereas no effects were observed on the insulin stimulated IRS1-Tyr and TSC2 Thr1462 phosphorylation. This is the first study to show that rapamycin reduces glucose uptake in human adipocytes through impaired insulin signalling and this may contribute to the development of insulin resistance associated with rapamycin therapy.
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| 10. |
- Pereira, Maria J, 1981, et al.
(författare)
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The immunosuppressive agents rapamycin, cyclosporin A and tacrolimus increase lipolysis, inhibit lipid storage and alter expression of genes involved in lipid metabolism in human adipose tissue.
- 2013
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Ingår i: Molecular and cellular endocrinology. - : Elsevier BV. - 1872-8057 .- 0303-7207. ; 365:2, s. 260-9
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Tidskriftsartikel (refereegranskat)abstract
- Cyclosporin A (CsA), tacrolimus and rapamycin are immunosuppressive agents (IAs) associated with insulin resistance and dyslipidemia, although their molecular effects on lipid metabolism in adipose tissue are unknown. We explored IAs effects on lipolysis, lipid storage and expression of genes involved on lipid metabolism in isolated human adipocytes and/or adipose tissue obtained via subcutaneous and omental fat biopsies. CsA, tacrolimus and rapamycin increased isoproterenol-stimulated lipolysis and inhibited lipid storage by 20-35% and enhanced isoproterenol-stimulated hormone-sensitive lipase Ser552 phosphorylation. Rapamycin also increased basal lipolysis (∼20%) and impaired insulin's antilipolytic effect. Rapamycin, down-regulated the gene expression of perilipin, sterol regulatory element-binding protein 1 (SREBP1) and lipin 1, while tacrolimus down-regulated CD36 and aP2 gene expression. All three IAs increased IL-6 gene expression and secretion, but not expression and secretion of TNF-α or adiponectin. These findings suggest that CsA, tacrolimus and rapamycin enhance lipolysis, inhibit lipid storage and expression of lipogenic genes in adipose tissue, which may contribute to the development of dyslipidemia and insulin resistance associated with immunosuppressive therapy.
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