| 1. |
- Adiels, Martin, 1976, et al.
(author)
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A new combined multicompartmental model for apolipoprotein B-100 and triglyceride metabolism in VLDL subfractions
- 2005
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In: J Lipid Res. - 0022-2275 .- 1539-7262. ; 46:1, s. 58-67
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Journal article (peer-reviewed)abstract
- The use of stable isotopes in conjunction with compartmental modeling analysis has greatly facilitated studies of the metabolism of the apolipoprotein B (apoB)-containing lipoproteins in humans. The aim of this study was to develop a multicompartment model that allows us to simultaneously determine the kinetics of apoB and triglyceride (TG) in VLDL(1) and VLDL(2) after a bolus injection of [(2)H(3)]leucine and [(2)H(5)]glycerol and to follow the catabolism and transfer of the lipoprotein particles. Here, we describe the model and present the results of its application in a fasting steady-state situation in 17 subjects with lipid values representative of a Western population. Analysis of the correlations showed that plasma TG was determined by the VLDL(1) and VLDL(2) apoB and TG fractional catabolic rate. Furthermore, the model showed a linear correlation between VLDL(1) TG and apoB production. A novel observation was that VLDL TG entered the circulation within 21 min after its synthesis, whereas VLDL apoB entered the circulation after 33 min. These observations are consistent with a sequential assembly model of VLDL and suggest that the TG is added to a primordial apoB-containing particle in the liver.
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| 2. |
- Adiels, Martin, 1976, et al.
(author)
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Acute suppression of VLDL(1) secretion rate by insulin is associated with hepatic fat content and insulin resistance
- 2007
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 50:11, s. 2356-2365
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Journal article (peer-reviewed)abstract
- AIMS/HYPOTHESIS: Overproduction of VLDL(1) seems to be the central pathophysiological feature of the dyslipidaemia associated with type 2 diabetes. We explored the relationship between liver fat and suppression of VLDL(1) production by insulin in participants with a broad range of liver fat content. METHODS: A multicompartmental model was used to determine the kinetic parameters of apolipoprotein B and TG in VLDL(1) and VLDL(2) after a bolus of [(2)H(3)]leucine and [(2)H(5)]glycerol during a hyperinsulinaemic-euglycaemic clamp in 20 male participants: eight with type 2 diabetes and 12 control volunteers. The participants were divided into two groups with low or high liver fat. All participants with diabetes were in the high liver-fat group. RESULTS: The results showed a rapid drop in VLDL(1)-apolipoprotein B and -triacylglycerol secretion in participants with low liver fat during the insulin infusion. In contrast, participants with high liver fat showed no significant change in VLDL(1) secretion. The VLDL(1) suppression following insulin infusion correlated with the suppression of NEFA, and the ability of insulin to suppress the plasma NEFA was impaired in participants with high liver fat. A novel finding was an inverse response between VLDL(1) and VLDL(2) secretion in participants with low liver fat: VLDL(1) secretion decreased acutely after insulin infusion whereas VLDL(2) secretion increased. CONCLUSIONS/INTERPRETATION: Insulin downregulates VLDL(1) secretion and increases VLDL(2) secretion in participants with low liver fat but fails to suppress VLDL(1) secretion in participants with high liver fat, resulting in overproduction of VLDL(1). Thus, liver fat is associated with lack of VLDL(1) suppression in response to insulin.
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| 3. |
- Adiels, Martin, 1976, et al.
(author)
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Diabetic dyslipidaemia
- 2006
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In: Curr Opin Lipidol. - 0957-9672 .- 1473-6535. ; 17:3, s. 238-46
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Journal article (peer-reviewed)abstract
- PURPOSE OF REVIEW: Diabetic dyslipidaemia is a cluster of plasma lipid and lipoprotein abnormalities that are metabolically interrelated. The increase of large type 1 very low density lipoprotein particles in type 2 diabetes initiates a sequence of events that generates atherogenic remnants, small dense low-density lipoprotein and small dense high-density lipoprotein particles. Thus, it is of great importance to elucidate the mechanisms behind the overproduction of large very low density lipoprotein particles in diabetic dyslipidaemia. This review discusses the pathophysiology of very low density lipoprotein metabolism in type 2 diabetes and recent concepts of lipid management of diabetic dyslipidaemia. RECENT FINDINGS: Results indicate that triglyceride and apolipoprotein B production in types 1 and 2 very low density lipoprotein are significantly correlated, suggesting a coupling of the two processes governing the metabolism of these lipoprotein subpopulations. Insulin resistance, hyperglycaemia, and liver fat were associated with excess hepatic production of type 1 but not type 2 very low density lipoprotein particles. These data provide support for the independent regulation of types 1 and 2 very low density lipoprotein apolipoprotein B production. SUMMARY: Recent data suggest that the assembly of very low density lipoprotein is fundamentally altered in type 2 diabetes, explaining the overproduction of large type 1 very low density lipoprotein as well as the inability of insulin to suppress production of type 1 very low density lipoprotein in type 2 diabetes. Future discoveries hopefully will delineate the regulatory steps to allow more targeted treatment of diabetic dyslipidaemia.
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| 4. |
- Adiels, Martin, 1976, et al.
(author)
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Niacin action in the atherogenic mixed dyslipidemia of metabolic syndrome: Insights from metabolic biomarker profiling and network analysis
- 2018
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In: Journal of Clinical Lipidology. - : Elsevier BV. - 1933-2874. ; 12:3, s. 810-821
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Journal article (peer-reviewed)abstract
- BACKGROUND: Niacin as an adjunct to statin treatment to reduce cardiovascular risk is questioned. OBJECTIVE: To evaluate interrelationships between the effects of niacin on mixed dyslipidemia and a spectrum of metabolic and inflammatory biomarkers. METHODS: Obese, nondiabetic, hypertriglyceridemic males (n = 19) with low high-density lipoprotein cholesterol levels received extended-release nicotinic acid for 8 weeks. Multiple biomarkers were measured using enzyme-linked immunosorbent assay, enzymatic/absorptiometric, or multiplex biochip assays. Treatment effects were determined for each variable and a differential correlation network created on the basis of univariate correlations between baseline and response to niacin treatment for all pairs of variables. RESULTS: Extended-release niacin treatment favoured normalization of plasma lipid and apolipoprotein profile. Plasma markers of inflammation, hepatic function, cellular adhesion and proliferation, and macrophage phenotype were attenuated; however, insulin resistance increased. Differential network analysis revealed that changes in triglycerides and high-density lipoprotein cholesterol were closely linked; equally, niacin mediated reductions in total cholesterol, apolipoprotein B, low-density lipoprotein cholesterol and lipoprotein(a) clustered together, as did homeostatic model assessment of insulin resistance, insulin, and interleukin-6 levels. Two clusters of inflammatory markers were identified, involving (1) intercellular adhesion molecule 1 and high-sensitive C-reactive protein and (2) soluble tumor necrosis factor receptors; and novel clusters involving matrix metallopeptidase 9 and apolipoprotein E, and adiponectin and cystatin C, respectively, were equally revealed. At lower stringency, lipid and insulin resistance clusters were linked; a C-reactive protein-centered cluster linked reduction in apolipoprotein Cu to intercellular adhesion molecule 1, gamma-glutamyltransferase, soluble tumor necrosis factor receptors, and E-selectin. CONCLUSION: A niacin-mediated trend to normalize atherogenic mixed dyslipidemia was intimately linked to attenuation of biomarkers of inflammation, cell adhesion, hepatic dysfunction and cell proliferation, but to enhanced insulin resistance and plasma homocysteine elevation. (C) 2018 National Lipid Association. Published by Elsevier Inc.
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| 5. |
- Adiels, Martin, 1976, et al.
(author)
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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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In: Rapid communications in mass spectrometry : RCM. - : Wiley. - 1097-0231 .- 0951-4198. ; 24:5, s. 586-592
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Journal article (peer-reviewed)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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| 6. |
- Adiels, Martin, 1976, et al.
(author)
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Overproduction of large VLDL particles is driven by increased liver fat content in man
- 2006
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 49:4, s. 755-65
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Journal article (peer-reviewed)abstract
- AIMS/HYPOTHESIS: We determined whether hepatic fat content and plasma adiponectin concentration regulate VLDL(1) production. METHODS: A multicompartment model was used to simultaneously determine the kinetic parameters of triglycerides (TGs) and apolipoprotein B (ApoB) in VLDL(1) and VLDL(2) after a bolus of [(2)H(3)]leucine and [(2)H(5)]glycerol in ten men with type 2 diabetes and in 18 non-diabetic men. Liver fat content was determined by proton spectroscopy and intra-abdominal fat content by MRI. RESULTS: Univariate regression analysis showed that liver fat content, intra-abdominal fat volume, plasma glucose, insulin and HOMA-IR (homeostasis model assessment of insulin resistance) correlated with VLDL(1) TG and ApoB production. However, only liver fat and plasma glucose were significant in multiple regression models, emphasising the critical role of substrate fluxes and lipid availability in the liver as the driving force for overproduction of VLDL(1) in subjects with type 2 diabetes. Despite negative correlations with fasting TG levels, liver fat content, and VLDL(1) TG and ApoB pool sizes, adiponectin was not linked to VLDL(1) TG or ApoB production and thus was not a predictor of VLDL(1) production. However, adiponectin correlated negatively with the removal rates of VLDL(1) TG and ApoB. CONCLUSIONS/INTERPRETATION: We propose that the metabolic effect of insulin resistance, partly mediated by depressed plasma adiponectin levels, increases fatty acid flux from adipose tissue to the liver and induces the accumulation of fat in the liver. Elevated plasma glucose can further increase hepatic fat content through multiple pathways, resulting in overproduction of VLDL(1) particles and leading to the characteristic dyslipidaemia associated with type 2 diabetes.
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| 7. |
- Adiels, Martin, 1976, et al.
(author)
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Overproduction of VLDL1 driven by hyperglycemia is a dominant feature of diabetic dyslipidemia
- 2005
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In: Arterioscler Thromb Vasc Biol. - 1524-4636 .- 1079-5642. ; 25:8, s. 1697-703
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Journal article (peer-reviewed)abstract
- OBJECTIVE: We sought to compare the synthesis and metabolism of VLDL1 and VLDL2 in patients with type 2 diabetes mellitus (DM2) and nondiabetic subjects. METHODS AND RESULTS: We used a novel multicompartmental model to simultaneously determine the kinetics of apolipoprotein (apo) B and triglyceride (TG) in VLDL1 and VLDL2 after a bolus injection of [2H3]leucine and [2H5]glycerol and to follow the catabolism and transfer of the lipoprotein particles. Our results show that the overproduction of VLDL particles in DM2 is explained by enhanced secretion of VLDL1 apoB and TG. Direct production of VLDL2 apoB and TG was not influenced by diabetes per se. The production rates of VLDL1 apoB and TG were closely related, as were the corresponding pool sizes. VLDL1 and VLDL2 compositions did not differ in subjects with DM2 and controls, and the TG to apoB ratio of newly synthesized particles was very similar in the 2 groups. Plasma glucose, insulin, and free fatty acids together explained 55% of the variation in VLDL1 TG production rate. CONCLUSIONS: Insulin resistance and DM2 are associated with excess hepatic production of VLDL1 particles similar in size and composition to those in nondiabetic subjects. We propose that hyperglycemia is the driving force that aggravates overproduction of VLDL1 in DM2.
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| 8. |
- Adiels, Martin, 1976, et al.
(author)
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Postprandial accumulation of chylomicrons and chylomicron remnants is determined by the clearance capacity.
- 2012
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In: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 222:1, s. 222-8
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Journal article (peer-reviewed)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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| 9. |
- Adiels, Martin, 1976, et al.
(author)
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Role of apolipoprotein C-III overproduction in diabetic dyslipidaemia
- 2019
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In: Diabetes, obesity and metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 21:8, s. 1861-1870
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Journal article (peer-reviewed)abstract
- - Aims: To investigate how apolipoprotein C-III (apoC-III) metabolism is altered in subjects with type 2 diabetes, whether the perturbed plasma triglyceride concentrations in this condition are determined primarily by the secretion rate or the removal rate of apoC-III, and whether improvement of glycaemic control using the glucagon-like peptide-1 analogue liraglutide for 16 weeks modifies apoC-III dynamics. Materials and Methods: Postprandial apoC-III kinetics were assessed after a bolus injection of [5,5,5- 2 H 3 ]leucine using ultrasensitive mass spectrometry techniques. We compared apoC-III kinetics in two situations: in subjects with type 2 diabetes before and after liraglutide therapy, and in type 2 diabetic subjects with matched body mass index (BMI) non-diabetic subjects. Liver fat content, subcutaneous abdominal and intra-abdominal fat were determined using proton magnetic resonance spectroscopy. Results: Improved glycaemic control by liraglutide therapy for 16 weeks significantly reduced apoC-III secretion rate (561 ± 198 vs. 652 ± 196 mg/d, P = 0.03) and apoC-III levels (10.0 ± 3.8 vs. 11.7 ± 4.3 mg/dL, P = 0.035) in subjects with type 2 diabetes. Change in apoC-III secretion rate was significantly associated with the improvement in indices of glucose control (r = 0.67; P = 0.009) and change in triglyceride area under the curve (r = 0.59; P = 0.025). In line with this, the apoC-III secretion rate was higher in subjects with type 2 diabetes compared with BMI-matched non-diabetic subjects (676 ± 208 vs. 505 ± 174 mg/d, P = 0.042). Conclusions: The results reveal that the secretion rate of apoC-III is associated with elevation of triglyceride-rich lipoproteins in subjects with type 2 diabetes, potentially through the influence of glucose homeostasis on the production of apoC-III. © 2019 John Wiley & Sons Ltd
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| 10. |
- Ahlin, Sofie, 1985, et al.
(author)
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Adipose Tissue-Derived Human Serum Amyloid A Does Not Affect Atherosclerotic Lesion Area in hSAA(+/) (-/)ApoE(-/-) Mice
- 2014
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In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:4
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Journal article (peer-reviewed)abstract
- Chronically elevated serum levels of serum amyloid A (SAA) are linked to increased risk of cardiovascular disease. However, whether SAA is directly involved in atherosclerosis development is still not known. The aim of this study was to investigate the effects of adipose tissue-derived human SAA on atherosclerosis in mice. hSAA1(+/-) transgenic mice (hSAA1 mice) with a specific expression of human SAA1 in adipose tissue were bred with ApoE-deficient mice. The hSAA1 mice and their wild type (wt) littermates were fed normal chow for 35 weeks. At the end of the experiment, the mice were euthanized and blood, gonadal adipose tissue and aortas were collected. Plasma levels of SAA, cholesterol and triglycerides were measured. Atherosclerotic lesion areas were analyzed in the aortic arch, the thoracic aorta and the abdominal aorta in en face preparations of aorta stained with Sudan IV. The human SAA protein was present in plasma from hSAA1 mice but undetectable in wt mice. Similar plasma levels of cholesterol and triglycerides were observed in hSAA1 mice and their wt controls. There were no differences in atherosclerotic lesion areas in any sections of the aorta in hSAA1 mice compared to wt mice. In conclusion, our data suggest that adipose tissue-derived human SAA does not influence atherosclerosis development in mice.
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