| 1. |
- Adiels, Martin, 1976, et al.
(författare)
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Optimization of N-methyl-N-[tert-butyldimethylsilyl]trifluoroacetamide as a derivatization agent for determining isotopic enrichment of glycerol in very-low density lipoproteins.
- 2010
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Ingår i: Rapid communications in mass spectrometry : RCM. - : Wiley. - 1097-0231 .- 0951-4198. ; 24:5, s. 586-592
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Tidskriftsartikel (refereegranskat)abstract
- Stable isotope kinetic studies play an important role in the study of very-low density lipoprotein (VLDL) metabolism, including basic and clinical research. Today, [1,1,2,3,3-(2)H(5)]glycerol is the most cost-effective alternative to measure glycerol and triglyceride kinetics. Recycling of glycerol from glycolysis and gluconeogenesis may lead to incompletely labelled tracer molecules. Many existing methods for the measurement of glycerol isotopic enrichment involve the production of glycerol derivatives that result in fragmentation of the glycerol molecule after ionization. It would be favourable to measure the intact tracer molecule since incompletely labelled tracer molecules may be measured as fully labelled. The number of methods available to measure the intact tracer in biological samples is limited. The aim of this project was to develop a gas chromatography/mass spectrometry (GC/MS) method for glycerol enrichment that measures the intact glycerol backbone and is suitable for electron ionization (EI), which is widely available. A previously published method for N-methyl-N-[tert-butyldimethylsilyl]trifluoroacetamide (MTBSTFA) derivatization was significantly improved; we produced a stable derivative and increased recovery 27-fold in standards. We used the optimized MTBSTFA method in VLDL-triglyceride and found that further modification was required to take matrix effects into account. We now have a robust method to measure glycerol isotopic enrichment by GC/EI-MS that can be used to rule out the known problem of tracer recycling in studies of VLDL kinetics. Copyright (c) 2010 John Wiley & Sons, Ltd.
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| 2. |
- Adiels, Martin, 1976, et al.
(författare)
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Postprandial accumulation of chylomicrons and chylomicron remnants is determined by the clearance capacity.
- 2012
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Ingår i: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 222:1, s. 222-8
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Tidskriftsartikel (refereegranskat)abstract
- Objective To better understand the postprandial clearance of triglyceride-rich lipoproteins (TRLs) and its relation to the fasting kinetics of TRLs. Methods Two studies were performed on 30 male subjects: a fasting kinetic study to determine the fasting secretion and clearance rates of apolipoprotein B (apoB) 100 and triglycerides in the very low-density lipoprotein 1 and 2 (VLDL1 and VLDL2) fractions; and a postprandial study to determine the postprandial accumulation of apoB48, apoB100 and triglycerides in the chylomicron, VLDL1 and VLDL2 fractions. Results from these two studies were combined to characterize the postprandial clearance of TRLs in a physiologically relevant setting. Results Our results show that postprandial accumulation of the apoB48-carrying chylomicrons can be predicted from the clearance capacity of the lipolytic pathway, determined in the fasting state. Furthermore, we show that chylomicrons and VLDL1 particles are not cleared equally by the lipoprotein lipase pathway, and that chylomicrons seem to be the preferred substrate. Subjects with a rapid fasting lipid metabolism accumulate lower levels of postprandial triglycerides with less accumulation of apoB100 in the VLDL1 fraction and a faster transfer of apoB100 into the VLDL2 fraction. In contrast, fasting VLDL1 secretion does not predict postprandial triglyceride accumulation. Conclusions Non-fasting triglyceride levels have recently been identified as a major predictor of future cardiovascular events. Here we show that the capacity of the lipolytic pathway is a common determinant of both the fasting and non-fasting triglyceride levels and may thus play an important role in the development of dyslipemia and atherosclerosis.
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| 3. |
- Ahmadpour, Doryaneh, 1973, et al.
(författare)
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Inhibition of MAPK Hog1 Results in Increased Hsp104 Aggregate Formation Probably through Elevated Arsenite Influx into the Cells, an Approach with Numerous Potential Applications
- 2014
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Ingår i: American Journal of Molecular Biology. - : Scientific Research Publishing, Inc.. - 2161-6620 .- 2161-6663. ; 4:2, s. 59-71
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Tidskriftsartikel (refereegranskat)abstract
- Arsenic is a highly toxic and carcinogenic metalloid widely dispersed in the environment, contaminating water and soil and accumulating in crops. Paradoxically, arsenic is also part of modern therapy and employed in treating numerous ailments and diseases. Hence, inventing strategies to tune cellular arsenic uptake based on purpose is striking. Here, we describe an approach in which the arsenite uptake can be increased using a MAPK inhibitor. Employing microfluidic flow chambers in combination with optical tweezers and fluorescent microscopy, we elevated the influx of arsenite into the yeast Saccharomyces cerevisiae cells following short-term treatment with a Hog1 kinase inhibitor. The increase in arsenite uptake was followed on arsenite triggered redistribution of a reporter protein, Hsp104-GFP, which was imaged over time. The effect was even more pronounced when the yeast mother and daughter cells were analyzed disjointedly, an opportunity provided owing to single-cell analysis. Our data firstly provide a strategy to increase arsenite uptake and secondly show that arsenite triggered aggregates, previously shown to be sites of damaged proteins, are distributed asymmetrically and less accumulated in daughter cells. Inventing approaches to tune arsenite uptake has a great value for its use in environmental as well as medical applications.
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| 4. |
- Berglund, Martin, 1980, et al.
(författare)
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Investigations of a compartmental model for leucine kinetics using non-linear mixed effects models with ordinary and stochastic differential equations.
- 2012
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Ingår i: Mathematical Medicine and Biology. - : Oxford University Press (OUP). - 1477-8599 .- 1477-8602. ; 29:4, s. 361-384
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Tidskriftsartikel (refereegranskat)abstract
- Non-linear mixed effects (NLME) models represent a powerful tool to simultaneously analyse data from several individuals. In this study, a compartmental model of leucine kinetics is examined and extended with a stochastic differential equation to model non-steady-state concentrations of free leucine in the plasma. Data obtained from tracer/tracee experiments for a group of healthy control individuals and a group of individuals suffering from diabetes mellitus type 2 are analysed. We find that the interindividual variation of the model parameters is much smaller for the NLME models, compared to traditional estimates obtained from each individual separately. Using the mixed effects approach, the population parameters are estimated well also when only half of the data are used for each individual. For a typical individual, the amount of free leucine is predicted to vary with a standard deviation of 8.9% around a mean value during the experiment. Moreover, leucine degradation and protein uptake of leucine is smaller, proteolysis larger and the amount of free leucine in the body is much larger for the diabetic individuals than the control individuals. In conclusion, NLME models offers improved estimates for model parameters in complex models based on tracer/tracee data and may be a suitable tool to reduce data sampling in clinical studies.
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| 5. |
- Borén, Jan, 1963, et al.
(författare)
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Kinetic Studies to Investigate Lipoprotein Metabolism.
- 2012
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Ingår i: Journal of internal medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 271:2, s. 166-173
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Forskningsöversikt (refereegranskat)abstract
- To develop novel strategies for prevention and treatment of dyslipidaemia, it is essential to understand the pathophysiology of dyslipoproteinaemia in humans. Lipoprotein metabolism is a complex system in which abnormal concentrations of various lipoprotein particles can result from alterations in their rates of production, conversion and/or catabolism. Traditional methods that measure plasma lipoprotein concentrations only provide static estimates of lipoprotein metabolism and hence limited mechanistic information. By contrast, the use of tracers labelled with stable isotopes and mathematical modelling provides a powerful tool for probing lipid and lipoprotein kinetics in vivo and furthering understanding of the pathogenesis of dyslipoproteinaemia.
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| 6. |
- Borén, Jan, 1963, et al.
(författare)
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Lipid metabolism in metabolic syndrome
- 2014
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Ingår i: A Systems Biology Approach to Study Metabolic Syndrome. - Cham : Springer. - 9783319010083 ; , s. 157-170
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Lipoprotein metabolism is a complex system in which abnormal concentrations of various lipoprotein particles can result from alterations in their rates of production, conversion and/or catabolism. To develop novel strategies for the prevention and treatment of dyslipidaemia, it is essential to better understand the lipid disorders in humans. Here we discuss recent advances in the field as well as show how the use of tracers labeled with stable isotopes combined with mathematical modelling provides a powerful tool for probing lipid and lipoprotein kinetics in vivo; thus furthering our understanding of the pathogenesis of lipid disorders. © Springer International Publishing Switzerland 2014.
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| 7. |
- Borén, Jan, 1963, et al.
(författare)
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Postprandial hypertriglyceridemia as a coronary risk factor.
- 2014
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Ingår i: Clinica chimica acta; international journal of clinical chemistry. - : Elsevier BV. - 1873-3492. ; 431, s. 131-42
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Forskningsöversikt (refereegranskat)abstract
- Postprandial hypertriglyceridemia is now established as an important risk factor for cardiovascular disease (CVD). This metabolic abnormality is principally initiated by overproduction and/or decreased catabolism of triglyceride-rich lipoproteins (TRLs) and is a consequence of predisposing genetic variations and medical conditions such as obesity and insulin resistance. Accumulation of TRLs in the postprandial state promotes the retention of remnant particles in the artery wall. Because of their size, most remnant particles cannot cross the endothelium as efficiently as smaller low-density lipoprotein (LDL) particles. However, since each remnant particle contains approximately 40 times more cholesterol compared with LDL, elevated levels of remnants may lead to accelerated atherosclerosis and CVD. The recognition of postprandial hypertriglyceridemia in the clinical setting has been severely hampered by technical difficulties and the lack of established clinical protocols for investigating postprandial lipemia. In addition, there are currently no internationally agreed management guidelines for this type of dyslipidemia. Here we review the mechanism for and consequences of excessive postprandial hypertriglyceridemia, epidemiological evidence in support of high triglycerides and remnant particles as risk factors for CVD, the definition of hypertriglyceridemia, methods to measure postprandial hypertriglyceridemia and apolipoproteins and, finally, current and future treatment opportunities.
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| 8. |
- Burza, Maria Antonella, 1980, et al.
(författare)
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PNPLA3 I148M (rs738409) genetic variant is associated with hepatocellular carcinoma in obese individuals
- 2012
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Ingår i: Digestive and Liver Disease. - : Elsevier BV. - 1590-8658. ; 44:12, s. 1037-1041
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Tidskriftsartikel (refereegranskat)abstract
- Background: Obesity is a risk factor for cancer, including hepatocellular carcinoma. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) genetic variant has been associated with hepatocellular carcinoma (HCC) in individuals with chronic alcohol abuse or hepatic viral infection. In the present study we examined the association between the PNPLA3I148M genetic variant and hepatocellular carcinoma in obese individuals from the Swedish Obese Subjects cohort (n=4047). Methods: We performed a matched, prospective, controlled, interventional trial, investigating the effect of bariatric surgery (surgery group) compared to conventional treatment (control group) for obesity. Results: A total of 9 events were observed in the 15-year median follow up (5 in the control group and 4 in the surgery group). A significantly higher incidence of hepatocellular carcinoma in PNPLA3 148M allele carriers was found in obese individuals in the control group (log-rank P-value=0.001), but not in the surgery group (log-rank P-value=0.783). Consistently, an increased risk (for each PNPLA3 148M allele, hazard ratio: 5.9; 95% confidence interval 1.5-23.8; P-value=0.013) of developing hepatocellular carcinoma was observed only in the control group. Conclusion: The current study is the first prospective report showing the association of the PNPLA3I148M genetic variant and hepatocellular carcinoma in severely obese individuals.
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| 9. |
- Granér, Marit, et al.
(författare)
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Cardiac steatosis associates with visceral obesity in nondiabetic obese men.
- 2013
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 98:3, s. 1189-97
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Tidskriftsartikel (refereegranskat)abstract
- Background: Liver fat and visceral adiposity are involved in the development of the metabolic syndrome (MetS). Ectopic fat accumulation within and around the heart has been related to increased risk of heart disease. The aim of this study was to explore components of cardiac steatosis and their relationship to intra-abdominal ectopic fat deposits and cardiometabolic risk factors in nondiabetic obese men. Methods: Myocardial and hepatic triglyceride (TG) contents were measured with 1.5 T magnetic resonance spectroscopy, and visceral adipose (VAT), abdominal subcutaneous tissue (SAT), epicardial and pericardial fat by magnetic resonance imaging in 37 men with the MetS and in 40 men without the MetS. Results: Myocardial and hepatic TG contents, VAT, SAT, epicardial fat volumes, and pericardial fat volumes were higher in men with the MetS compared with subjects without the MetS (P < .001). All components of cardiac steatosis correlated with SAT, VAT, and hepatic TG content and the correlations seemed to be strongest with VAT. Myocardial TG content, epicardial fat, pericardial fat, VAT, and hepatic TG content correlated with waist circumference, body mass index, high-density lipoprotein cholesterol TGs, very low-density lipoprotein-1 TGs, and the insulin-resistance homeostasis model assessment index. VAT was a predictor of TGs, high-density lipoprotein cholesterol, and measures of glucose metabolism, whereas age and SAT were determinants of blood pressure parameters. Conclusions: We suggest that visceral obesity is the best predictor of epicardial and pericardial fat in abdominally obese subjects. Myocardial TG content may present a separate entity that is influenced by factors beyond visceral adiposity.
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| 10. |
- Henningsson, Louise, 1979, et al.
(författare)
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Interleukin 15 Mediates Joint Destruction in Staphylococcus Aureus Arthritis
- 2012
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 206:5, s. 687-696
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Tidskriftsartikel (refereegranskat)abstract
- Background. Staphylococcus aureus arthritis causes severe and rapid joint damage despite antibiotics. Thus, there is a need to identify new treatment targets in addition to antibiotics. Lately, interleukin 15 (IL-15) has been implicated both in osteoclastogenesis and in bacterial clearance-2 important issues in S. aureus-induced joint destruction. This has prompted us to investigate the importance of IL-15 in S. aureus-induced arthritis. Methods.Toxic shock syndrome toxin-1 producing S. aureus was intravenously inoculated in IL-15 knockout and wildtype mice and in wildtype mice treated with anti-IL-15 antibodies (aIL-15ab) or isotype control antibody. Results.Absence of IL-15, either in knockout mice or after treatment with aIL-15ab, significantly reduced weight loss compared with controls during the infection. The severity of synovitis and joint destruction was significantly decreased in IL-15 knockout and aIL-15ab treated mice compared with controls. In IL-15 knockout mice there was a reduced number of osteoclasts in the joints. The host's ability to clear bacteria was not influenced in the IL-15 knockout mice, but significantly increased after treatment with aIL-15ab. Conclusions.IL-15 is a mediator of joint destruction in S. aureus-induced arthritis and contributes to general morbidity, which makes this cytokine an interesting treatment target in addition to conventional antibiotics.
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