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  • 1. Aberg, Wiveca
    et al.
    Thörne, Anders
    Olivecrona, Thomas
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Fysiologisk kemi.
    Nordenström, Jörgen
    Fat oxidation and plasma removal capacity of an intravenous fat emulsion in elderly and young men.2006Inngår i: Nutrition, ISSN 0899-9007, Vol. 22, nr 7-8, 738-43 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 2.
    Andersson, Eva-Lotta
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Hernell, Olle
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Bläckberg, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Fält, Helen
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Lindquist, Susanne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Bile salt-stimulated lipase and pancreatic lipase-related protein 2: key enzymes for lipid digestion in the newborn examined using the Caco-2 cell line2011Inngår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 52, nr 11, 1949-1956 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In rodents, bile salt-stimulated lipase (BSSL) and pancreatic lipase-related protein 2 (PLRP2) are the dominant lipases expressed in the exocrine pancreas in early life, when milk is the main food. The aim of the present study was to evaluate if BSSL and PLRP2 are also key enzymes in neonatal intestinal fat digestion. Using Caco-2 cells as a model for the small intestinal epithelium, purified human enzymes were incubated in the apical chamber with substrates and bile salt concentrations resembling the milieu of the small intestine of newborn infants. BSSL and PLRP2 hydrolyzed triglycerides (TG) to free fatty acids (FA) and glycerol. The cells took up the FA, which were reesterfied to TG. Together, BSSL and PLRP2 have a synergistic effect, increasing cellular uptake 4-fold compared to the sum of each lipase alone. A synergistic effect was also observed with retinyl ester as a substrate. PLRP2 hydrolyzed cholesteryl ester but not as efficiently as BSSL, and the two had an additive rather than synergistic effect. We conclude the key enzymes in intestinal fat digestion are different in newborns than later in life. Further studies are needed to fully understand this difference and its implication for designing optimal neonatal nutrition.

  • 3. Avall, Karin
    et al.
    Ali, Yusuf
    Leibiger, Ingo B.
    Leibiger, Barbara
    Moede, Tilo
    Paschen, Meike
    Dicker, Andrea
    Dare, Elisabetta
    Kohler, Martin
    Ilegems, Erwin
    Abdulreda, Midhat H.
    Graham, Mark
    Crooke, Rosanne M.
    Tay, Vanessa S. Y.
    Refai, Essam
    Nilsson, Stefan K.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Jacob, Stefan
    Selander, Lars
    Berggren, Per-Olof
    Juntti-Berggren, Lisa
    Apolipoprotein CIII links islet insulin resistance to beta-cell failure in diabetes2015Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, nr 20, E2611-E2619 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Insulin resistance and beta-cell failure are the major defects in type 2 diabetes mellitus. However, the molecular mechanisms linking these two defects remain unknown. Elevated levels of apolipoprotein CIII (apoCIII) are associated not only with insulin resistance but also with cardiovascular disorders and inflammation. We now demonstrate that local apoCIII production is connected to pancreatic islet insulin resistance and beta-cell failure. An increase in islet apoCIII causes promotion of a local inflammatory milieu, increased mitochondrial metabolism, deranged regulation of beta-cell cytoplasmic free Ca2+ concentration ([Ca2+](i)) and apoptosis. Decreasing apoCIII in vivo results in improved glucose tolerance, and pancreatic apoCIII knockout islets transplanted into diabetic mice, with high systemic levels of the apolipoprotein, demonstrate a normal [Ca2+](i) response pattern and no hallmarks of inflammation. Hence, under conditions of islet insulin resistance, locally produced apoCIII is an important diabetogenic factor involved in impairment of beta-cell function and may thus constitute a novel target for the treatment of type 2 diabetes mellitus.

  • 4. Bartelt, Alexander
    et al.
    John, Clara
    Schaltenberg, Nicola
    Berbee, Jimmy F. P.
    Worthmann, Anna
    Cherradi, M. Lisa
    Schlein, Christian
    Piepenburg, Julia
    Boon, Mariette R.
    Rinninger, Franz
    Heine, Markus
    Toedter, Klaus
    Niemeier, Andreas
    Nilsson, Stefan K.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi. Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
    Fischer, Markus
    Wijers, Sander L.
    Lichtenbelt, Wouter van Marken
    Scheja, Ludger
    Rensen, Patrick C. N.
    Heeren, Joerg
    Thermogenic adipocytes promote HDL turnover and reverse cholesterol transport2017Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, 15010Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Brown and beige adipocytes combust nutrients for thermogenesis and through their metabolic activity decrease pro-atherogenic remnant lipoproteins in hyperlipidemic mice. However, whether the activation of thermogenic adipocytes affects the metabolism and anti-atherogenic properties of high-density lipoproteins (HDL) is unknown. Here, we report a reduction in atherosclerosis in response to pharmacological stimulation of thermogenesis linked to increased HDL levels in APOE(star)3-Leiden. CETP mice. Both cold-induced and pharmacological thermogenic activation enhances HDL remodelling, which is associated with specific lipidomic changes in mouse and human HDL. Furthermore, thermogenic stimulation promotes HDL-cholesterol clearance and increases macrophage-to-faeces reverse cholesterol transport in mice. Mechanistically, we show that intravascular lipolysis by adipocyte lipoprotein lipase and hepatic uptake of HDL by scavenger receptor B-I are the driving forces of HDL-cholesterol disposal in liver. Our findings corroborate the notion that high metabolic activity of thermogenic adipocytes confers atheroprotective properties via increased systemic cholesterol flux through the HDL compartment.

  • 5. Berg, Kirsti
    et al.
    Ericsson, Madelene
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Lindgren, Mikael
    Gustafsson, Håkan
    A High Precision Method for Quantitative Measurements of Reactive Oxygen Species in Frozen Biopsies2014Inngår i: PLoS ONE, ISSN 1932-6203, Vol. 9, nr 3, e90964- s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: An electron paramagnetic resonance (EPR) technique using the spin probe cyclic hydroxylamine 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine (CMH) was introduced as a versatile method for high precision quantification of reactive oxygen species, including the superoxide radical in frozen biological samples such as cell suspensions, blood or biopsies. Materials and Methods: Loss of measurement precision and accuracy due to variations in sample size and shape were minimized by assembling the sample in a well-defined volume. Measurement was carried out at low temperature (150 K) using a nitrogen flow Dewar. The signal intensity was measured from the EPR 1st derivative amplitude, and related to a sample, 3-carboxy-proxyl (CPN) with known spin concentration. Results: The absolute spin concentration could be quantified with a precision and accuracy better than +/- 10 mu M (k = 1). The spin concentration of samples stored at -80 degrees C could be reproduced after 6 months of storage well within the same error estimate. Conclusion: The absolute spin concentration in wet biological samples such as biopsies, water solutions and cell cultures could be quantified with higher precision and accuracy than normally achievable using common techniques such as flat cells, tissue cells and various capillary tubes. In addition; biological samples could be collected and stored for future incubation with spin probe, and also further stored up to at least six months before EPR analysis, without loss of signal intensity. This opens for the possibility to store and transport incubated biological samples with known accuracy of the spin concentration over time.

  • 6. Berthiaume, Magalie
    et al.
    Laplante, Mathieu
    Festuccia, William T
    Cianflone, Katherine
    Turcotte, Lorraine P
    Joanisse, Denis R
    Olivecrona, Gunilla
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Fysiologisk kemi.
    Thieringer, Rolf
    Deshaies, Yves
    11beta-HSD1 inhibition improves triglyceridemia through reduced liver VLDL secretion and partitions lipids toward oxidative tissues.2007Inngår i: Am J Physiol Endocrinol Metab, ISSN 0193-1849, Vol. 293, nr 4, E1045-52 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 7. Blanchard, P. G.
    et al.
    Turcotte, V.
    Cote, M.
    Gelinas, Y.
    Nilsson, S.
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Deshaies, Y.
    Festuccia, W. T.
    Peroxisome proliferator-activated receptor activation favours selective subcutaneous lipid deposition by coordinately regulating lipoprotein lipase modulators, fatty acid transporters and lipogenic enzymes2016Inngår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 217, nr 3, 227-239 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: Peroxisome proliferator-activated receptor (PPAR) γ activation is associated with preferential lipoprotein lipase (LPL)-mediated fatty acid storage in peripheral subcutaneous fat depots. How PPARγ agonism acts upon the multi-level modulation of depot-specific lipid storage remains incompletely understood.

    Methods: We evaluated herein triglyceride-derived lipid incorporation into adipose tissue depots, LPL mass and activity, mRNA levels and content of proteins involved in the modulation of LPL activity and fatty acid transport, and the expression/activity of enzymes defining adipose tissue lipogenic potential in rats treated with the PPARγ ligand rosiglitazone (30 mg kg−1 day−1, 23 days) after either a 10-h fasting period or a 17-h fast followed by 6 h of ad libitum refeeding.

    Results: Rosiglitazone stimulated lipid accretion in subcutaneous fat (SF) ~twofold and significantly reduced that of visceral fat (VF) to nearly half. PPARγ activation selectively increased LPL mass, activity and the expression of its chaperone LMF1 in SF. In VF, rosiglitazone had no effect on LPL activity and downregulated the mRNA levels of the transendothelial transporter GPIHBP1. Overexpression of lipid uptake and fatty acid transport proteins (FAT/CD36, FATP1 and FABP4) and stimulation of lipogenic enzyme activities (GPAT, AGPAT and DGAT) upon rosiglitazone treatment were of higher magnitude in SF.

    Conclusions: Together these findings demonstrate that the depot-specific transcriptional control of LPL induced by PPARγ activation extends to its key interacting proteins and post-translational modulators to favour subcutaneous lipid storage.

  • 8.
    Blind, Per Jonas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Bläckberg, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Hernell, Olle
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Ljungberg, Börje
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Carboxylic ester hydrolase: a serum marker of acute pancreatitis1987Inngår i: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 2, nr 5, 597-603 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    By use of an enzyme-linked immunosorbent assay we established serum reference values of carboxylic ester hydrolase, a pancreatic secretory lipolytic enzyme, and explored to see if a raised serum level is indicative of acute pancreatitis. Postoperative elevation of carboxylic ester hydrolase was observed in seven out of ten patients who underwent pancreatic surgery. Serum levels of carboxylic ester hydrolase and amylase were determined in 129 patients admitted due to abdominal emergency conditions. Amylase was elevated in 27 patients, and in 20 of these raised carboxylic ester hydrolase levels affirmed the diagnosis acute pancreatitis. In five out of the seven patients with elevated amylase alone no etiologic factor of acute pancreatitis was found. Another 11 patients had raised carboxylic ester hydrolase levels without concomitant elevation of amylase. In all these patients, a likely cause of pancreatic inflammation was identifiable. Hence, a raised carboxylic ester hydrolase level, even in presence of normal amylase, could be indicative of acute pancreatic inflammation.

  • 9. Blind, Per-Jonas
    et al.
    Büchler, M
    Bläckberg, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Andersson, Yvonne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Uhl, W
    Beger, H G
    Hernell, Olle
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Carboxylic ester hydrolase. A sensitive serum marker and indicator of severity of acute pancreatitis.1991Inngår i: International journal of Pancreatology, ISSN 0169-4197, Vol. 8, nr 1, 65-73 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    When using clinical criteria, both falsely positive and falsely negative diagnoses of acute pancreatitis (AP) are often made. Based on a clinical study, elevated serum levels of the pancreatic lipolytic enzyme carboxylic ester hydrolase (CEH) was recently suggested to be a highly specific marker of acute pancreatitis. To determine the sensitivity of the test for AP, a study on patients with the diagnosis set objectively was necessary. In the present study, AP was diagnosed by contrast-enhanced computed tomography in 64 patients, and histopathological examination of tissue removed at laparotomy in 18 of them. By these criteria, 42 patients suffered from acute interstitial pancreatitis (AIP), and 22 patients from necrotizing pancreatitis (NP). Based on the CEH concentrations in the first serum sample obtained in each patient, the sensitivity of CEH for pancreatitis was 98%. From the second day after admission, CEH levels in patients with NP were significantly higher than in patients with AIP. Furthermore, in patients with NP, CEH values remained at a raised level for the following 10 d, whereas a significant decrease of CEH values was noted in patients with AIP. In contrast, total serum amylase activities were higher in patients suffering of AIP than in patients suffering of NP during the observation period. We conclude, that the sensitivity of the CEH test is very high for AP. CEH concentrations remaining at a high level are suggestive of NP, whereas diminishing CEH levels are suggestive of AIP.

  • 10.
    Blomquist, Caroline
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Chorell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Ryberg, Mats
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Mellberg, Caroline
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Worrsjö, Evelina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Makoveichuk, Elena
    Larsson, Christel
    Lindahl, Bernt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Olsson, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Decreased lipogenesis-promoting factors in adipose tissue in postmenopausal women with overweight on a Paleolithic-type diet.2017Inngår i: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: We studied effects of diet-induced postmenopausal weight loss on gene expression and activity of proteins involved in lipogenesis and lipolysis in adipose tissue.

    METHODS: Fifty-eight postmenopausal women with overweight (BMI 32.5 ± 5.5) were randomized to eat an ad libitum Paleolithic-type diet (PD) aiming for a high intake of protein and unsaturated fatty acids or a prudent control diet (CD) for 24 months. Anthropometry, plasma adipokines, gene expression of proteins involved in fat metabolism in subcutaneous adipose tissue (SAT) and lipoprotein lipase (LPL) activity and mass in SAT were measured at baseline and after 6 months. LPL mass and activity were also measured after 24 months.

    RESULTS: The PD led to improved insulin sensitivity (P < 0.01) and decreased circulating triglycerides (P < 0.001), lipogenesis-related factors, including LPL mRNA (P < 0.05), mass (P < 0.01), and activity (P < 0.001); as well as gene expressions of CD36 (P < 0.05), fatty acid synthase, FAS (P < 0.001) and diglyceride acyltransferase 2, DGAT2 (P < 0.001). The LPL activity (P < 0.05) and gene expression of DGAT2 (P < 0.05) and FAS (P < 0.05) were significantly lowered in the PD group versus the CD group at 6 months and the LPL activity (P < 0.05) remained significantly lowered in the PD group compared to the CD group at 24 months.

    CONCLUSIONS: Compared to the CD, the PD led to a more pronounced reduction of lipogenesis-promoting factors in SAT among postmenopausal women with overweight. This could have mediated the favorable metabolic effects of the PD on triglyceride levels and insulin sensitivity.

  • 11.
    Bläckberg, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Fat digestion in the newborn infant: with special reference to the bile salt-stimulated lipase and the milk fat globule1981Doktoravhandling, med artikler (Annet vitenskapelig)
  • 12.
    Brattsand, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Dermatologi och venereologi.
    Stefansson, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Dermatologi och venereologi.
    Hubiche, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Dermatologi och venereologi.
    Nilsson, Stefan K
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Egelrud, Torbjörn
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Dermatologi och venereologi.
    SPINK9: a selective, skin-specific Kazal-type serine protease inhibitor.2009Inngår i: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 129, nr 7, 1656-1665 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A previously unreported Kazal-type serine protease inhibitor, serine protease inhibitor Kazal type 9 (SPINK9), was identified in human skin. SPINK9 expression was strong in palmar epidermis, but not detectable or very low in non palmoplantar skin. Analysis of a human cDNA panel showed intermediate expression in thymus, pancreas, liver, and brain, and low or undetectable expression in other tissues. Using kallikrein-related peptidases (KLKs) 5, 7, 8, and 14, thrombin, trypsin, and chymotrypsin, inhibition with recombinant SPINK9 was seen only for KLK5 using low molecular weight substrates, with an apparent K(i) of 65 nM. Also KLK5 degradation of fibrinogen was totally inhibited by SPINK9. Slight inhibition of KLK8 using fibrinogen substrate could be observed using high concentrations of SPINK9. Analyses by surface plasmon resonance showed heterogeneous binding to SPINK9 of KLK5 and KLK8, but no binding of KLK7 or KLK14. KLK5 has been suggested to play a central role in skin desquamation as an initiating activating enzyme in proteolytic cascades formed by KLKs. An apparently KLK5-specific inhibitor, such as SPINK9, may play a significant regulatory role in such cascades. We suggest a possible role for SPINK9 in the site-specific epidermal differentiation of palms and soles.

  • 13. Cantoni, Claudia
    et al.
    Bollman, Bryan
    Licastro, Danilo
    Xie, Mingqiang
    Mikesell, Robert
    Schmidt, Robert
    Yuede, Carla M.
    Galimberti, Daniela
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Klein, Robyn S.
    Cross, Anne H.
    Otero, Karel
    Piccio, Laura
    TREM2 regulates microglial cell activation in response to demyelination in vivo2015Inngår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 129, nr 3, 429-447 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2(-/-)) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2(-/-) microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2(-/-) microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage.

  • 14.
    Caraballo, Remi
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Larsson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Nilsson, Stefan K.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Ericsson, Madelene
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Qian, Weixing
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Tran, Nam Phuong Nguyen
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Kindahl, Tomas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Svensson, Richard
    Uppsala, Sweden.
    Saar, Valeria
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Artursson, Per
    Uppsala, Sweden.
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Enquist, Per-Anders
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Elofsson, Mikael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Structure-activity relationships for lipoprotein lipase agonists that lower plasma triglycerides in vivo2015Inngår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 103, 191-209 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The risk of cardiovascular events increases in individuals with elevated plasma triglyceride (TG) levels, therefore advocating the need for efficient TG-lowering drugs. In the blood circulation, TG levels are regulated by lipoprotein lipase (LPL), an unstable enzyme that is only active as a non-covalently associated homodimer. We recently reported on a N-phenylphthalimide derivative (1) that stabilizes LPL in vitro, and moderately lowers triglycerides in vivo (Biochem. Biophys. Res. Common. 2014, 450, 1063). Herein, we establish structure activity relationships of 51 N-phenylphthalimide analogs of the screening hit 1. In vitro evaluation highlighted that modifications on the phthalimide moiety were not tolerated and that lipophilic substituents on the central phenyl ring were functionally essential. The substitution pattern on the central phenyl ring also proved important to stabilize LPL However, in vitro testing demonstrated rapid degradation of the phthalimide fragment in plasma which was addressed by replacing the phthalimide scaffold with other heterocyclic fragments. The in vitro potency was retained or improved and substance 80 proved stable in plasma and efficiently lowered plasma TGs in vivo. 2015 The Authors. Published by Elsevier Masson SAS.

  • 15. Catoire, MilSNe
    et al.
    Alex, Sheril
    Paraskevopulos, Nicolas
    Mattijssen, Frits
    Evers-van Gogh, Inkie
    Schaart, Gert
    Jeppesen, Jacob
    Kneppers, Anita
    Mensink, Marco
    Voshol, Peter J.
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Tan, Nguan Soon
    Hesselink, Matthijs K. C.
    Berbee, Jimmy F.
    Rensen, Patrick C. N.
    Kalkhoven, Eric
    Schrauwen, Patrick
    Kersten, Sander
    Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise2014Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, nr 11, E1043-E1052 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Physical activity increases energy metabolism in exercising muscle. Whether acute exercise elicits metabolic changes in nonexercising muscles remains unclear. We show that one of the few genes that is more highly induced in nonexercising muscle than in exercising human muscle during acute exercise encodes angiopoietin-like 4 (ANGPTL4), an inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance. Using a combination of human, animal, and in vitro data, we show that induction of ANGPTL4 in nonexercising muscle is mediated by elevated plasma free fatty acids via peroxisome proliferator-activated receptor-delta, presumably leading to reduced local uptake of plasma triglyceride-derived fatty acids and their sparing for use by exercising muscle. In contrast, the induction of ANGPTL4 in exercising muscle likely is counteracted via AMP-activated protein kinase (AMPK)-mediated down-regulation, promoting the use of plasma triglycerides as fuel for active muscles. Our data suggest that nonexercising muscle and the local regulation of ANGPTL4 via AMPK and free fatty acids have key roles in governing lipid homeostasis during exercise.

  • 16.
    Chevreuil, O
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Hultin, M
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Ostergaard, P
    Olivecrona, T
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Biphasic effects of low-molecular-weight and conventional heparins on chylomicron clearance in rats.1993Inngår i: Arteriosclerosis and thrombosis : a journal of vascular biology / American Heart Association, ISSN 1049-8834, Vol. 13, nr 10, 1397-403 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chylomicrons labeled in vivo with [14C]triglycerides and [3H]retinyl esters were injected in rats at a series of times after administration of conventional unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or saline. In saline controls the clearance of both chylomicron triglycerides and retinyl esters seemed to follow exponential courses, with half-lives of about 5 and 10 minutes, respectively. Five minutes after administration of LMWH or UFH, the triglyceride clearance rates were dramatically increased and were associated with an increased appearance of the radiolabel in circulating free fatty acids (FFAs). The clearance of [3H]retinol radioactivity, ie, chylomicron particles, was also enhanced 5 minutes after heparin injection. From 75% to 90% disappeared from the circulation within the first 5 minutes. Their continued disappearance was much slower, with a slope similar to that of the saline-treated rats. Hence, it was as if a new, rapid exponent had been added to the disappearance curve that accounted for most of the particle clearance. Injection of chylomicrons 1 hour after the heparins resulted in substantially slower clearance compared with saline-treated controls of both triglyceride and retinol radioactivity in rats given a high dose of LMWH or a low dose of either heparin. Appearance of label in plasma FFAs was also decreased, suggesting that impeded lipolysis was responsible, at least in part, for the impeded chylomicron clearance. Four and 24 hours after heparin injection all studied parameters of chylomicron clearance had returned to normal.(ABSTRACT TRUNCATED AT 250 WORDS)

  • 17.
    Chevreuil, O
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Hultin, M
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Ostergaard, P
    Olivecrona, T
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Depletion of lipoprotein lipase after heparin administration.1993Inngår i: Arteriosclerosis and thrombosis : a journal of vascular biology / American Heart Association, ISSN 1049-8834, Vol. 13, nr 10, 1391-6 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Some or most of the turnover of lipoprotein lipase (LPL) occurs by dissociation from vascular endothelial sites in extrahepatic tissues and further degradation in the liver. Heparin greatly enhances this dissociation and delays but does not abolish uptake in the liver, raising the possibility that heparin could lead to accelerated catabolism of functional LPL. To investigate this, we determined time curves for heparin (anti-factor Xa activity) and for LPL and hepatic lipase after injection in rats of two doses of conventional unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). The high dose (250 U/kg) of both heparins resulted in similar initial levels of LPL activity in plasma, but at 30 minutes the activity with LMWH had declined by more than 80%, whereas with UFH it remained essentially unchanged during this time. In contrast, time curves for heparin activity in blood were similar for the two heparins. The low dose (50 U/kg) led to lower initial levels of LPL activity with LMWH in spite of slower elimination of heparin activity from the blood. These results agree with previous studies that indicate that LMWH has a similar ability as UFH to release LPL, but a lesser ability to delay its removal by the liver. Only slight differences were noted in the time curves for hepatic lipase with the two heparins. To assess the possible depletion of the lipases, we administered a second large dose of conventional heparin. One hour after the first injection, the second injection resulted in lower plasma LPL activities in all four groups.(ABSTRACT TRUNCATED AT 250 WORDS)

  • 18.
    Chevreuil, O
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Hultin, M
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Ostergaard, P
    Olivecrona, T
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Heparin-decasaccharides impair the catabolism of chylomicrons.1996Inngår i: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 320 ( Pt 2), 437-44 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    On intravenous injection to rats, decasaccharides gave rise to a short-lived peak of lipoprotein lipase (LPL) activity, whereas octa- and hexasaccharides caused only marginal increases. In isolated hearts perfused by a single pass, decasaccharides released LPL more efficiently than conventional heparin on a mass basis. Octa- and hexasaccharides were much less efficient. Similar results were obtained for hepatic lipase, which was studied both in vivo and by liver perfusion. In the intact rat, the heparin fragments themselves disappeared rapidly from the circulating blood. The decay of hepatic lipase activity after the early peak roughly paralleled the decay of decasaccharide concentration, but for LPL the decay was faster, presumably because the liver extracted this lipase from plasma. To assess the lipase activities remaining in contact with blood a large dose of conventional heparin was injected at a series of times after the decasaccharides. LPL was decreased by 40% after 1 h. At that time, the LPL activity that could be released from isolated hearts by single-pass perfusion with heparin for 2 min ("functional LPL') was decreased by 75%. Chylomicrons labelled in vivo with [14C]oleic acid (primarily in triacylglycerols, providing a tracer for lipolysis) and [3H]retinol (primarily in ester form, providing a tracer for the particles) were injected intravenously to explore the effects of the LPL depletion on lipoprotein metabolism. Triacylglycerol lipolysis and particle clearance was markedly delayed from 30 min to 2 h after injection of decasaccharides. After 1 h the fractional catabolic rate was only one-third of the control value and the catabolism of chylomicron triacylglycerols by perfused hearts was delayed to a similar extent. Thus injection of decasaccharides leads to accelerated turnover of LPL with loss of functional LPL from extrahepatic tissues. This in turn leads to a period of delayed lipolysis and removal of chylomicron particles.

  • 19.
    Christophersen, Bjørn
    et al.
    Institutt for klinisk biokjemi og Institutt for klinisk medisin, Rikshospitalet, Universitetet i Oslo.
    Sørby, Randi
    Seksjon for anatomi og patologi ved Norges veterinaerhögskole.
    Osmundsen, Harald
    Institutt for oral biologi, Odontologisk fakultet, Universitetet i Oslo.
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Nordstoga, Knut
    Hvorfor hypertriglyseridemi fø      rer til pankreatitt2013Inngår i: Tidsskrift for den Norske lægeforening : tidsskrift for praktisk medicin, ny række, ISSN 0807-7096, Vol. 133, nr 1, 14-15 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 20. Coca-Prieto, Inmaculada
    et al.
    Kroupa, Olessia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Gonzalez-Santos, Pedro
    Magne, Joëlle
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Ehrenborg, Ewa
    Valdivielso, Pedro
    Childhood-onset chylomicronaemia with reduced plasma lipoprotein lipase activity and mass: identification of a novel GPIHBP1 mutation2011Inngår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 270, nr 3, 224-228 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives:  Deficiency in the catabolism of triglyceride-rich lipoproteins is the main cause of childhood-onset chylomicronaemia syndrome. Missense mutations in lipoprotein lipase (LPL) or in proteins influencing LPL activity or stability have been shown to be critical determinants of chylomicronaemia syndrome. The main objective of the present study was to assess the primary deficiency in five cases of childhood-onset chylomicronaemia syndrome.

    Setting:  Lipid clinic at a university hospital,

    Subjects:  Subjects presenting with severe hypertriglyceridaemia and chylomicronaemia syndrome in which reduced LPL activity and mass was observed. Interventions:  Analysis of LPL and GPIHBP1 genes.

    Results:  Among the five patients, one novel homozygous missense mutation (p.C68Y) in exon 3 of GPIHBP1 was identified. The other four patients were homozygous for the common LPL mutation p.G188E.

    Conclusion:  These findings provide further evidence that GPIHBP1 is involved in the catabolism of triglyceride-rich lipoproteins and plays a role in childhood-onset chylomicronaemia.

  • 21.
    Coca-Prieto, Inmaculada
    et al.
    Unidad de Lípidos, Servicio de Medicina Interna, Hospital Virgen de la Victoria, Málaga and Departamento de Medicina, Universidad de Málaga, Malaga, Spain.
    Valdivielso, Pedro
    Unidad de Lípidos, Servicio de Medicina Interna, Hospital Virgen de la Victoria, Málaga and Departamento de Medicina, Universidad de Málaga, Malaga, Spain.
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Ariza, María José
    Laboratorio de Lípidos y Arteriosclerosis, Centro de Investigaciones Médico-Sanitarias, Universidad de Málaga, Malaga, Spain.
    Rioja, José
    Laboratorio de Lípidos y Arteriosclerosis, Centro de Investigaciones Médico-Sanitarias, Universidad de Málaga, Malaga, Spain.
    Font-Ugalde, Pilar
    Departamento de Medicina, Facultad de Medicina, Universidad de Córdoba, Cordoba, Spain.
    García-Arias, Carlota
    Unidad de Lípidos, Servicio de Medicina Interna, Hospital Virgen de la Victoria, Málaga and Departamento de Medicina, Universidad de Málaga, Malaga, Spain.
    González-Santos, Pedro
    Unidad de Lípidos, Servicio de Medicina Interna, Hospital Virgen de la Victoria, Málaga and Departamento de Medicina, Universidad de Málaga, Malaga, Spain.
    Lipoprotein lipase activity and mass, apolipoprotein C-II mass and polymorphisms of apolipoproteins E and A5 in subjects with prior acute hypertriglyceridaemic pancreatitis2009Inngår i: BMC Gastroenterology, ISSN 1471-230X, Vol. 9, 46- s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Severe hypertriglyceridaemia due to chylomicronemia may trigger an acute pancreatitis. However, the basic underlying mechanism is usually not well understood. We decided to analyze some proteins involved in the catabolism of triglyceride-rich lipoproteins in patients with severe hypertriglyceridaemia.

    METHODS: Twenty-four survivors of acute hypertriglyceridaemic pancreatitis (cases) and 31 patients with severe hypertriglyceridaemia (controls) were included. Clinical and anthropometrical data, chylomicronaemia, lipoprotein profile, postheparin lipoprotein lipase mass and activity, hepatic lipase activity, apolipoprotein C II and CIII mass, apo E and A5 polymorphisms were assessed.

    RESULTS: Only five cases were found to have LPL mass and activity deficiency, all of them thin and having the first episode in childhood. No cases had apolipoprotein CII deficiency. No significant differences were found between the non-deficient LPL cases and the controls in terms of obesity, diabetes, alcohol consumption, drug therapy, gender distribution, evidence of fasting chylomicronaemia, lipid levels, LPL activity and mass, hepatic lipase activity, CII and CIII mass or apo E polymorphisms. However, the SNP S19W of apo A5 tended to be more prevalent in cases than controls (40% vs. 23%, NS).

    CONCLUSION: Primary defects in LPL and C-II are rare in survivors of acute hypertriglyceridaemic pancreatitis; lipase activity measurements should be restricted to those having their first episode during childhood.

  • 22. Davies, Brandon S J
    et al.
    Beigneux, Anne P
    Barnes, Richard H
    Tu, Yiping
    Gin, Peter
    Weinstein, Michael M
    Nobumori, Chika
    Nyrén, Rakel
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Goldberg, Ira
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Bensadoun, André
    Young, Stephen G
    Fong, Loren G
    GPIHBP1 is responsible for the entry of lipoprotein lipase into capillaries.2010Inngår i: Cell metabolism, ISSN 1932-7420, Vol. 12, nr 1, 42-52 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The lipolytic processing of triglyceride-rich lipoproteins by lipoprotein lipase (LPL) is the central event in plasma lipid metabolism, providing lipids for storage in adipose tissue and fuel for vital organs such as the heart. LPL is synthesized and secreted by myocytes and adipocytes, but then finds its way into the lumen of capillaries, where it hydrolyzes lipoprotein triglycerides. The mechanism by which LPL reaches the lumen of capillaries has remained an unresolved problem of plasma lipid metabolism. Here, we show that GPIHBP1 is responsible for the transport of LPL into capillaries. In Gpihbp1-deficient mice, LPL is mislocalized to the interstitial spaces surrounding myocytes and adipocytes. Also, we show that GPIHBP1 is located at the basolateral surface of capillary endothelial cells and actively transports LPL across endothelial cells. Our experiments define the function of GPIHBP1 in triglyceride metabolism and provide a mechanism for the transport of LPL into capillaries.

  • 23. Dijk, Wieneke
    et al.
    Heine, Markus
    Vergnes, Laurent
    Boon, Mariëtte R.
    Schaart, Gert
    Hesselink, Matthijs K. C.
    Reue, Karen
    Lichtenbelt, Wouter D. van Marken
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Rensen, Patrick C. N.
    Heeren, Joerg
    Kersten, Sander
    ANGPTL4 mediates shuttling of lipid fuel to brown adipose tissue during sustained cold exposure2015Inngår i: eLIFE, E-ISSN 2050-084X, Vol. 4, e08428Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Brown adipose tissue (BAT) activation via cold exposure is increasingly scrutinized as a potential approach to ameliorate cardio-metabolic risk. Transition to cold temperatures requires changes in the partitioning of energy substrates, re-routing fatty acids to BAT to fuel non-shivering thermogenesis. However, the mechanisms behind the redistribution of energy substrates to BAT remain largely unknown. Angiopoietin-like 4 (ANGPTL4), a protein that inhibits lipoprotein lipase (LPL) activity, is highly expressed in BAT. Here, we demonstrate that ANGPTL4 is part of a shuttling mechanism that directs fatty acids derived from circulating triglyceride-rich lipoproteins to BAT during cold. Specifically, we show that cold markedly down-regulates ANGPTL4 in BAT, likely via activation of AMPK, enhancing LPL activity and uptake of plasma triglyceride-derived fatty acids. In contrast, cold up-regulates ANGPTL4 in WAT, abolishing a cold-induced increase in LPL activity. Together, our data indicate that ANGPTL4 is an important regulator of plasma lipid partitioning during sustained cold.

  • 24. Dorfmeister, B
    et al.
    Zeng, W W
    Dichlberger, A
    Nilsson, Stefan K
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Schaap, F G
    Hubacek, J A
    Merkel, M
    Cooper, J A
    Lookene, Aivar
    Putt, W
    Whittall, R
    Lee, P J
    Lins, L
    Delsaux, N
    Nierman, M
    Kuivenhoven, J A
    Kastelein, J J P
    Vrablik, M
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Schneider, W J
    Heeren, J
    Humphries, S E
    Talmud, P J
    Effects of six APOA5 variants, identified in patients with severe hypertriglyceridemia, on in vitro lipoprotein lipase activity and receptor binding2008Inngår i: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 28, nr 10, 1866-1871 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: The purpose of this study was to identify rare APOA5 variants in 130 severe hypertriglyceridemic patients by sequencing, and to test their functionality, since no patient recall was possible.

    METHODS AND RESULTS: We studied the impact in vitro on LPL activity and receptor binding of 3 novel heterozygous variants, apoAV-E255G, -G271C, and -H321L, together with the previously reported -G185C, -Q139X, -Q148X, and a novel construct -Delta139 to 147. Using VLDL as a TG-source, compared to wild type, apoAV-G255, -L321 and -C185 showed reduced LPL activation (-25% [P=0.005], -36% [P<0.0001], and -23% [P=0.02]), respectively). ApoAV-C271, -X139, -X148, and Delta139 to 147 had little affect on LPL activity, but apoAV-X139, -X148, and -C271 showed no binding to LDL-family receptors, LR8 or LRP1. Although the G271C proband carried no LPL and APOC2 mutations, the H321L carrier was heterozygous for LPL P207L. The E255G carrier was homozygous for LPL W86G, yet only experienced severe hypertriglyceridemia when pregnant.

    CONCLUSIONS: The in vitro determined function of these apoAV variants only partly explains the high TG levels seen in carriers. Their occurrence in the homozygous state, coinheritance of LPL variants or common APOA5 TG-raising variant in trans, appears to be essential for their phenotypic expression.

  • 25. Drager, Luciano F.
    et al.
    Li, Jianguo
    Shin, Mi-Kyung
    Reinke, Christian
    Aggarwal, Neil R.
    Jun, Jonathan C.
    Bevans-Fonti, Shannon
    Sztalryd, Carole
    OByrne, Sheila M.
    Kroupa, Olessia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Blaner, William S.
    Polotsky, Vsevolod Y.
    Intermittent hypoxia inhibits clearance of triglyceride-rich lipoproteins and inactivates adipose lipoprotein lipase in a mouse model of sleep apnoea2012Inngår i: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 33, nr 6, 783-U33 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Delayed lipoprotein clearance is associated with atherosclerosis. This study examined whether chronic intermittent hypoxia (CIH), a hallmark of obstructive sleep apnoea (OSA), can lead to hyperlipidaemia by inhibiting clearance of triglyceride rich lipoproteins (TRLP). Male C57BL/6J mice on high-cholesterol diet were exposed to 4 weeks of CIH or chronic intermittent air (control). FIO2 was decreased to 6.5 once per minute during the 12 h light phase in the CIH group. After the exposure, we measured fasting lipid profile. TRLP clearance was assessed by oral gavage of retinyl palmitate followed by serum retinyl esters (REs) measurements at 0, 1, 2, 4, 10, and 24 h. Activity of lipoprotein lipase (LpL), a key enzyme of lipoprotein clearance, and levels of angiopoietin-like protein 4 (Angptl4), a potent inhibitor of the LpL activity, were determined in the epididymal fat pads, skeletal muscles, and heart. Chronic intermittent hypoxia induced significant increases in levels of total cholesterol and triglycerides, which occurred in TRLP and LDL fractions (P 0.05 for each comparison). Compared with control mice, animals exposed to CIH showed increases in REs throughout first 10 h after oral gavage of retinyl palmitate (P 0.05), indicating that CIH inhibited TRLP clearance. CIH induced a 5-fold decrease in LpL activity (P 0.01) and an 80 increase in Angptl4 mRNA and protein levels in the epididymal fat, but not in the skeletal muscle or heart. CIH decreases TRLP clearance and inhibits LpL activity in adipose tissue, which may contribute to atherogenesis observed in OSA.

  • 26. Drager, Luciano F.
    et al.
    Yao, Qiaoling
    Hernandez, Karen L.
    Shin, Mi-Kyung
    Bevans-Fonti, Shannon
    Gay, Jason
    Sussan, Thomas E.
    Jun, Jonathan C.
    Myers, Allen C.
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Schwartz, Alan R.
    Halberg, Nils
    Scherer, Philipp E.
    Semenza, Gregg L.
    Powell, David R.
    Polotsky, Vsevolod Y.
    Chronic Intermittent Hypoxia Induces Atherosclerosis via Activation of Adipose Angiopoietin-like 42013Inngår i: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 188, nr 2, 240-248 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Rationale: Obstructive sleep apnea is a risk factor for dyslipidemia and atherosclerosis, which have been attributed to chronic intermittent hypoxia (CIH). Intermittent hypoxia inhibits a key enzyme of lipoprotein clearance, lipoprotein lipase, and up-regulates a lipoprotein lipase inhibitor, angiopoietin-like 4 (Angptl4), in adipose tissue. The effects and mechanisms of Angptl4 up-regulation in sleep apnea are unknown. Objectives: To examine whether CIH induces dyslipidemia and atherosclerosis by increasing adipose Angptl4 via hypoxia-inducible factor-1 (HIF-1). Methods: ApoE(-/-) mice were exposed to intermittent hypoxia or air for 4 weeks while being treated with Angptl4-neutralizing antibody or vehicle. Measurements and Main Results: In vehicle-treated mice, hypoxia increased adipose Angptl4 levels, inhibited adipose lipoprotein lipase, increased fasting levels of plasma triglycerides and very low density lipoprotein cholesterol, and increased the size of atherosclerotic plaques. The effects of CIH were abolished by the antibody. Hypoxia-induced increases in plasma fasting triglycerides and adipose Angptl4 were not observed in mice with germline heterozygosity for a HIF-1 alpha knockout allele. Transgenic overexpression of HIF-1 alpha in adipose tissue led to dyslipidemia and increased levels of adipose Angptl4. In cultured adipocytes, constitutive expression of HIF-1 alpha increased Angptl4 levels, which was abolished by siRNA. Finally, in obese patients undergoing bariatric surgery, the severity of nocturnal hypoxemia predicted Angptl4 levels in subcutaneous adipose tissue. Conclusions: HIF-1-mediated increase in adipose Angptl4 and the ensuing lipoprotein lipase in activation may contribute to atherosclerosis in patients with sleep apnea.

  • 27.
    Eriksson, Jan. W.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Burén, Jonas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Svensson, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Olivecrona, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Postprandial regulation of blood lipids and adipose tissue lipoprotein lipase in type 2 diabetes patients and healthy control subjects2003Inngår i: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 166, nr 2, 359-367 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background/aim: In type 2 diabetes and other insulin-resistant conditions, postprandial hypertriglyceridaemia is an important metabolic perturbation. To further elucidate alterations in the clearance of triglyceride-rich lipoproteins in type 2 diabetes we focused on the nutritional regulation of adipose tissue lipoprotein lipase (LPL).

    Subjects and methods: Eight subjects with type 2 diabetes and eight age-, sex- and body mass index (BMI)-matched control subjects underwent subcutaneous abdominal adipose tissue biopsies in the fasting state and 3.5 h following a standardized lipid-enriched meal. LPL activity and mass were measured in adipose tissue and also in plasma after an intravenous injection of heparin.

    Results: Postprandial, but not fasting, triglycerides were significantly higher in the diabetic subjects than in the control subjects (3.0±0.4 vs 2.0±0.2 mmol/l, P=0.028). Adipose tissue LPL activity was increased following the meal test by ∼35–55% (P=0.021 and 0.004, respectively). There was no significant difference between the groups in this respect. The specific enzyme activity of LPL was not altered in the postprandial state. Fasting and postprandial adipose tissue LPL activity as well as post-heparin plasma LPL activity tended to be lower among the diabetes patients (NS). There was a significant and independent inverse association between insulin resistance (homeostasis model assessment insulin resistance (HOMA-IR) index) vs post-heparin plasma LPL activity and postprandial triglyceride levels, respectively. Adipose tissue LPL activity was related to insulin action in vitro on adipocyte glucose transport, but not to HOMA-IR.

    Conclusion: Following food intake adipose tissue LPL activity is enhanced to a similar degree in patients with type 2 diabetes and in healthy control subjects matched for BMI, age and gender. If LPL dysregulation is involved in the postprandial hypertriglyceridaemia found in type 2 diabetes, it should occur in tissues other than subcutaneous fat.

  • 28. Fredriksson, H
    et al.
    Ikonen, T
    Autio, V
    Matikainen, M P
    Helin, H J
    Tammela, T L J
    Koivisto, P A
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Fysiologisk kemi.
    Schleutker, J
    Identification of germline MLH1 alterations in familial prostate cancer.2006Inngår i: Eur J Cancer, ISSN 0959-8049, Vol. 42, nr 16, 2802-6 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 29.
    Fugmann, Cecilia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Effect of a low-carbohydrate high-fat diet on exercise capacity and metabolic response after high-intensity interval training in C57Bl/6J mice2013Independent thesis Advanced level (professional degree), 20 poäng / 30 hpOppgave
  • 30. Gangabadage, Chinthaka Saneth
    et al.
    Zdunek, Janusz
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Tessari, Marco
    Nilsson, Solveig
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Wijmenga, Sybren Sipke
    Structure and dynamics of human apolipoprotein CIII2008Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 283, nr 25, 17416-17427 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human apolipoprotein CIII (apoCIII) is a surface component of chylomicrons, very low density lipoproteins, and high density lipoproteins. ApoCIII inhibits lipoprotein lipase as well as binding of lipoproteins to cell surface heparan sulfate proteoglycans and receptors. High levels of apoCIII are often correlated with elevated levels of blood lipids (hypertriglyceridemia). Here, we report the three-dimensional NMR structure and dynamics of human apo-CIII in complex with SDS micelles, mimicking its natural lipid-bound state. Thanks to residual dipolar coupling data, the first detailed view is obtained of the structure and dynamics of an intact apolipoprotein in its lipid-bound state. ApoCIII wraps around the micelle surface as a necklace of six approximately 10-residue amphipathic helices, which are curved and connected via semiflexible hinges. Three positively charged (Lys) residues line the polar faces of helices 1 and 2. Interestingly, their three-dimensional conformation is similar to that of the low density lipoprotein receptor binding motifs of apoE/B and the receptor-associated protein. At the C-terminal side of apoCIII, an array of negatively charged residues lines the polar faces of helices 4 and 5 and the adjacent flexible loop. Sequence comparison shows that this asymmetric charge distribution along the solvent-exposed face of apoCIII as well as other structural features are conserved among mammals. This structure provides a template for exploration of molecular mechanisms by which human apoCIII inhibits lipoprotein lipase and receptor binding.

  • 31. Gewert, Karin
    et al.
    Gregory, Peter C
    Olivecrona, Gunilla
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Fysiologisk kemi.
    Erlanson-Albertsson, Charlotte
    Pierzynowski, Stefan G
    Specificity of the 3H-triolein assay for pancreatic lipase in blood plasma.2005Inngår i: Clin Chem Lab Med, ISSN 1434-6621, Vol. 43, nr 11, 1211-4 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 32. Gewert, Karin
    et al.
    Holowachuk, Scott A
    Rippe, Catarina
    Gregory, Peter C
    Erlanson-Albertsson, Charlotte
    Olivecrona, Gunilla
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Fysiologisk kemi.
    Kruszewska, Danuta
    Piedra, Jose Valverde
    Weström, Björn
    Pierzynowski, Stefan G
    The enzyme levels in blood are not affected by oral administration of a pancreatic enzyme preparation (Creon 10,000) in pancreas-insufficient pigs.2004Inngår i: Pancreas, ISSN 1536-4828, Vol. 28, nr 1, 80-8 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 33.
    Gistera, A.
    et al.
    Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Robertson, A. K.
    Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Andersson, J.
    Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Ketelhuth, D. F. J.
    Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Oychinnikova, O.
    Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Nilsson, Stefan K
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Lundberg, A. M.
    Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Li, M. O.
    Department of Immunobiology, Yale University School of Medicine, New Haven CT, USA.
    Flavell, R. A.
    Department of Immunobiology, Yale University School of Medicine, New Haven CT, USA.
    Hansson, G. K.
    Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Transforming growth factor-beta signaling in t cells promotes stabilization of atherosclerotic plaques through an interleukin-17 dependent pathway2014Inngår i: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 235, nr 2, E88-E89 s.Artikkel i tidsskrift (Annet vitenskapelig)
  • 34. Gisterå, Anton
    et al.
    Robertson, Anna-Karin L
    Andersson, John
    Ketelhuth, Daniel FJ
    Ovchinnikova, Olga
    Nilsson, Stefan K
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Lundberg, Anna M
    Li, Ming O
    Flavell, Richard A
    Hansson, Göran K
    Transforming growth factor-beta signaling in T cells promotes stabilization of atherosclerotic plaques through an interleukin-17-dependent pathway2013Inngår i: Science Translational Medicine, ISSN 1946-6234, Vol. 5, nr 196, 196ra100- s.Artikkel i tidsskrift (Fagfellevurdert)
  • 35. Gordts, Philip L S M
    et al.
    Bartelt, Alexander
    Nilsson, Stefan K
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Annaert, Wim
    Christoffersen, Christina
    Nielsen, Lars Bo
    Heeren, Joerg
    Roebroek, Anton J M
    Impaired LDL Receptor-Related Protein 1 Translocation Correlates with Improved Dyslipidemia and Atherosclerosis in apoE-Deficient Mice2012Inngår i: PLoS ONE, ISSN 1932-6203, Vol. 7, nr 6, e38330- s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: Determination of the in vivo significance of LDL receptor-related protein 1 (LRP1) dysfunction on lipid metabolism and atherosclerosis development in absence of its main ligand apoE.

    METHODS AND RESULTS: LRP1 knock-in mice carrying an inactivating mutation in the NPxYxxL motif were crossed with apoE-deficient mice. In the absence of apoE, relative to LRP1 wild-type animals, LRP1 mutated mice showed an increased clearance of postprandial lipids despite a compromised LRP1 endocytosis rate and inefficient insulin-mediated translocation of the receptor to the plasma membrane, likely due to inefficient slow recycling of the mutated receptor. Postprandial lipoprotein improvement was explained by increased hepatic clearance of triglyceride-rich remnant lipoproteins and accompanied by a compensatory 1.6-fold upregulation of LDLR expression in hepatocytes. One year-old apoE-deficient mice having the dysfunctional LRP1 revealed a 3-fold decrease in spontaneous atherosclerosis development and a 2-fold reduction in LDL-cholesterol levels.

    CONCLUSION: These findings demonstrate that the NPxYxxL motif in LRP1 is important for insulin-mediated translocation and slow perinuclear endosomal recycling. These LRP1 impairments correlated with reduced atherogenesis and cholesterol levels in apoE-deficient mice, likely via compensatory LDLR upregulation.

  • 36.
    Guggenheimer, Denise
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Levels of angiopoietin-like protein 4 in blood at different stages of pregnancy  2013Independent thesis Advanced level (professional degree), 20 poäng / 30 hpOppgave
  • 37. Gustafsson, Maria
    et al.
    Levin, Malin
    Skålén, Kristina
    Perman, Jeanna
    Fridén, Vincent
    Jirholt, Pernilla
    Olofsson, Sven-Olof
    Fazio, Sergio
    Linton, MacRae F
    Semenkovich, Clay F
    Olivecrona, Gunilla
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Fysiologisk kemi.
    Borén, Jan
    Retention of low-density lipoprotein in atherosclerotic lesions of the mouse: evidence for a role of lipoprotein lipase.2007Inngår i: Circ Res, ISSN 1524-4571, Vol. 101, nr 8, 777-83 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 38.
    Hartelius, Jana
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    The impact of High intensity training on lipids and blood glucose in mice lacking ApoA-V2013Independent thesis Advanced level (professional degree), 20 poäng / 30 hpOppgave
  • 39.
    Hellström, Martin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Ericsson, Madelene
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Johansson, Bengt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Faraz, Mahmood
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Anderson, Fredrick
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. Regional Cancer Center Stockholm/Gotland, Stockholm, Sweden.
    Nilsson, Stefan K.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Cardiac hypertrophy and decreased high-density lipoprotein cholesterol in Lrig3-deficient mice2016Inngår i: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 310, nr 11, R1045-R1052 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genetic factors confer risk for cardiovascular disease. Recently, large genome-wide population studies have shown associations between genomic loci close to LRIG3 and heart failure and plasma high-density lipoprotein (HDL) cholesterol level. Here, we ablated Lrig3 in mice and investigated the importance of Lrig3 for heart function and plasma lipid levels. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze Lrig3 expression in the hearts of wild-type and Lrig3-deficient mice. In addition, molecular, physiological, and functional parameters such as organ weights, heart rate, blood pressure, heart structure and function, gene expression in the heart, and plasma insulin, glucose, and lipid levels were evaluated. The Lrig3-deficient mice were smaller than the wild-type mice but otherwise appeared grossly normal. Lrig3 was expressed at detectable but relatively low levels in adult mouse hearts. At 9 mo of age, ad libitum-fed Lrig3-deficient mice had lower insulin levels than wildtype mice. At 12 mo of age, Lrig3-deficient mice exhibited increased blood pressure, and the Lrig3-deficient female mice displayed signs of cardiac hypertrophy as assessed by echocardiography, heart-to-body weight ratio, and expression of the cardiac hypertrophy marker gene Nppa. Additionally, Lrig3-deficient mice had reduced plasma HDL cholesterol and free glycerol. These findings in mice complement the human epidemiological results and suggest that Lrig3 may influence heart function and plasma lipid levels in mice and humans.

  • 40.
    Hernell, Olle
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Bläckberg, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Bernbäck, S
    Digestion of human milk fat in early infancy1989Inngår i: Acta paediatrica Scandinavica. Supplement, ISSN 0300-8843, Vol. 351, 57-62 s.Artikkel i tidsskrift (Fagfellevurdert)
  • 41.
    Hertz, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    ApoE knockout mice on high fat diet demonstrates a blunted response to high-intensity interval training.2012Independent thesis Advanced level (professional degree), 20 poäng / 30 hpOppgave
  • 42. Heverin, Maura
    et al.
    Ali, Zeina
    Olin, Maria
    Tillander, Veronika
    Joibari, Masoumeh Motamedi
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Makoveichuk, Elena
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Leitersdorf, Eran
    Warner, Margret
    Olivercrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Gustafsson, Jan-Åke
    Björkhem, Ingemar
    On the regulatory importance of 27-hydroxycholesterol in mouse liver2017Inngår i: Journal of Steroid Biochemistry and Molecular Biology, ISSN 0960-0760, E-ISSN 1879-1220, Vol. 169, 10-21 s.Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    27-Hydroxycholesterol (27OH) is a strong suppressor of cholesterol synthesis and a weak activator of LXR in vitro. The regulatory importance of 27OH in vivo is controversial. Here we utilized male mice with increased levels of 27OH either due to increased production (CYP27A1 transgenic mice) or reduced metabolism (Cyp7b1-/- mice). We also used mice lacking 27OH due to a knockout of Cyp27a1. The latter mice were treated with cholic acid to compensate for reduced bile acid synthesis. The effects of the different levels of 27OH on Srebp- and other LXR-regulated genes in the liver were investigated. In the liver of CYP27tg mice we found a modest increase of the mRNA levels corresponding to the LXR target genes Cyp7b1 and Abca1. A number of other LXR-regulated genes were not affected. The effect on Abca1 mRNA was not seen in the liver of Cyp7b1-/- mice. There were little or no effects on cholesterol synthesis. In the liver of the Cyp27-/- mice treated with 0.025% cholic acid there was no significant effect of the knockout on the LXR target genes. In a previous work triple-knockout mice deficient in the biosynthesis of 24S-hydroxycholesterol, 25-hydroxycholesterol and 27OH were shown to have impaired response to dietary cholesterol, suggesting side-chain oxidized oxysterols to be mediators in cholesterol-induced effects on LXR target genes at a transcriptional level (Chen W. et al., Cell Metab. 5 (2007) 73-79). The hydroxylated oxysterol responsible for the effect was not defined. We show here that treatment of wildtype mice with dietary cholesterol under the same conditions as in the above study induced the LXR target genes Lpl, Abcg8 and Srebp1c in wild type mice but failed to activate the same genes in mice lacking 27-hydroxycholesterol due to a knockout of Cyp27. We failed to demonstrate the above effects at the protein level (Abcg8) or at the activity level (Lpl). The results suggest that 27OH is not an important regulator of Srebp- or LXR regulated genes under basal conditions in mouse liver. On the other hand 27OH appears to mediate cholesterol-induced effects on some LXR target genes at a transcriptional level under some in vivo conditions. 

  • 43. Holmberg, Rebecka
    et al.
    Refai, Essam
    Höög, Anders
    Crooke, Rosanne M
    Graham, Mark
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Berggren, Per-Olof
    Juntti-Berggren, Lisa
    Lowering apolipoprotein CIII delays onset of type 1 diabetes2011Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, nr 26, 10685-10689 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Serum levels of apolipoprotein CIII (apoCIII) are increased in type 1 diabetic patients, and when β cells are exposed to these diabetic sera, apoptosis occurs, an effect abolished by an antibody against apoCIII. We have investigated the BB rat, an animal model that develops a human-like type 1 diabetes, and found that apoCIII was also increased in sera from prediabetic rats. This increase in apoCIII promoted β-cell death. The endogenous levels of apoCIII were reduced by treating prediabetic animals with an antisense against this apolipoprotein, resulting in a significantly delayed onset of diabetes. ApoCIII thus serves as a diabetogenic factor, and intervention with this apolipoprotein in the prediabetic state can arrest disease progression. These findings suggest apoCIII as a target for the treatment of type 1 diabetes.

  • 44.
    Hultin, M
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Bengtsson-Olivecrona, G
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Olivecrona, T
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Release of lipoprotein lipase to plasma by triacylglycerol emulsions. Comparison to the effect of heparin.1992Inngår i: Biochimica et Biophysica Acta, ISSN 0006-3002, Vol. 1125, nr 1, 97-103 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    It was previously known that lipoprotein lipase (LPL) activity in plasma rises after infusion of a fat emulsion. To explore the mechanism we have compared the release of LPL by emulsion to that by heparin. After bolus injections of a fat emulsion (Intralipid) to rats, plasma LPL activity gradually rose 5-fold to a maximum at 6-8 min. During the same time the concentration of injected triacylglycerols (TG) decreased by about half. Hence, the time-course for plasma LPL activity was quite different from that for plasma TG. The disappearance of injected 125I-labelled bovine LPL from circulation was retarded by emulsion. This effect was more marked 30 min than 3 min after injection of the emulsion. The data indicate that the release of LPL into plasma is not solely due to binding of the lipase to the emulsion particles as such, but involves metabolism of the particles. Emulsion increased the fraction of labelled LPL found in adipose tissue, heart and the red muscle studied, but had no significant effect on the fraction found in liver. The effects of emulsion were quite different from those of heparin, which caused an immediate release of the lipase to plasma, decreased uptake of LPL in most extrahepatic tissues by 60-95%, and increased the fraction taken up in the liver.

  • 45.
    Hultin, M
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Carneheim, C
    Rosenqvist, K
    Olivecrona, T
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Intravenous lipid emulsions: removal mechanisms as compared to chylomicrons.1995Inngår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 36, nr 10, 2174-84 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have compared the metabolism of chylomicrons and a labeled emulsion, similar to those used for parenteral nutrition. Both were labeled in their triglyceride moieties and by a core label. It is known that chylomicron triglycerides are cleared by two processes: removal of triglycerides from the particles through lipolysis and removal of whole or partly lipolyzed particles. It has been proposed that emulsion droplets are cleared by the same pathways. After intravenous injection to postprandial rats, triglycerides were cleared less rapidly from the emulsion than from the chylomicrons (half-lives of 6.4 and 4.0 min), whereas the core labels were cleared at the same rate (half-lives around 7.5 min). This suggests that there was less lipolysis of the emulsion droplets which was further supported by the finding that less label appeared in the plasma free fatty acids (FFA). In adipose tissue of fed rats given chylomicrons, the ratio between fatty acid and core label was above 6, showing that fatty acids had been taken up after lipoprotein lipase-mediated hydrolysis. In contrast, for rats given emulsion, that ratio was only 1.2 showing that nearly as much emulsion droplets as emulsion-derived fatty acids were present in the tissue. In the liver the ratio was 0.55 after chylomicrons but 0.93 after emulsion. In further support of more lipolysis, fatty acids were oxidized more rapidly from chylomicrons than from emulsion. These data suggest that a large fraction of the emulsion droplets was removed from plasma with little or no preceding lipolysis. A substantial proportion, more than 50%, of this uptake occurred in extrahepatic tissues.

  • 46.
    Hultin, M
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Müllertz, A
    Zundel, M A
    Olivecrona, G
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Hansen, T T
    Deckelbaum, R J
    Carpentier, Y A
    Olivecrona, T
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Metabolism of emulsions containing medium- and long-chain triglycerides or interesterified triglycerides.1994Inngår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 35, nr 10, 1850-60 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This study compares the clearing and metabolism of three different lipid emulsions. They had the same phospholipid emulsifier and similar particle sizes. In one (LLL) the core component was long-chain triglycerides (TG), the second (MMM/LLL) contained equal molar amounts of medium- and long-chain TG, the third (MLM) contained synthetic TG with medium-chain (M) fatty acids in the 1,3-positions and a long-chain (L) fatty acid in the 2-position. In model experiments with bovine lipoprotein lipase, the MMM component was hydrolyzed preferentially in the MMM/LLL emulsion so that the initial products were M fatty acids and M monoglycerides. The MLM emulsion, in contrast, gave M fatty acids and formation of L-MG (monoglyceride) throughout hydrolysis. For in vivo studies [3H]oleic acid was incorporated into the emulsion TG as marker for the long-chain component. After bolus injection to rats, the MMM/LLL and MLM emulsions were cleared more rapidly than the LLL emulsion. This was true at all TG loads studied (4-64 mg for a 200 g rat). The labeled oleic acid was oxidized somewhat more rapidly when administered in the MLM emulsion compared to the MMM/LLL emulsion. There were only slight differences in tissue distribution of label. Hence, differences in in vivo metabolism of the long-chain fatty acids were small compared to the marked differences in TG structure and in patterns of product release during in vitro lipolysis.

  • 47.
    Hultin, M
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Olivecrona, G
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Olivecrona, T
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Effect of protamine on lipoprotein lipase and hepatic lipase in rats.1994Inngår i: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 304 ( Pt 3), 959-66 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The polycation protamine impedes the catabolism of triglyceride-rich lipoproteins and this has been suggested to be due to intravascular inactivation of lipoprotein lipase. We have made intravenous injections of protamine to rats and found that both lipoprotein lipase and hepatic lipase activities were released to plasma. The effect of protamine was more short-lived than that obtained by injection of heparin. The release of hepatic lipase by protamine was as effective as the release by heparin, while the amount of lipoprotein lipase released by protamine was only about one-tenth of that released by heparin. This was not due to inactivation of lipoprotein lipase, since injection of an excess of heparin 10 min after injection of protamine released as much lipoprotein lipase activity to plasma as in controls. The results in vivo differed from those obtained in model experiments in vitro. Protamine was able to almost quantitatively release both lipoprotein lipase and hepatic lipase from columns of heparin-agarose. The displacement was dependent on the total amount of protamine that had passed over the column, indicating that it was due to occupation by protamine of all available binding sites. Our results in vivo showed that the binding sites for lipoprotein lipase were not blocked as efficiently as those for hepatic lipase, indicating that the binding structures were not identical. It was concluded that the impaired turnover of lipoproteins by protamine probably was due to prevention of binding of the lipoproteins to endothelial cell surfaces rather than to impaired lipase function.

  • 48.
    Hultin, M
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Olivecrona, T
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Conversion of chylomicrons into remnants.1998Inngår i: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 141 Suppl 1, S25-9 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The turnover of chylomicrons in the blood is the sum of several processes. The native chylomicron is synthesized in the intestine out of available substrates. When the chylomicron enters the circulation exchanges of apolipoproteins with other lipoproteins, it also binds to the vascular endothelium where the chylomicron is lipolyzed by lipoprotein lipase. After a short period in the circulation the chylomicron/chylomicron remnant appears to be available for receptor mediated uptake. In this paper several of the processes involved in generation and clearance of chylomicron remnants are discussed.

  • 49.
    Hultin, M
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Savonen, R
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Olivecrona, T
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Chylomicron metabolism in rats: lipolysis, recirculation of triglyceride-derived fatty acids in plasma FFA, and fate of core lipids as analyzed by compartmental modelling.1996Inngår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 37, nr 5, 1022-36 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chylomicrons labeled in vivo with [14C]oleic acid (primarily in triglycerides (TG), providing a tracer for lipolysis) and [3H]retinol (primarily in ester form, providing a tracer for the corelipids) were injected into rats. Disappearance of the two labels from plasma and appearance of label in plasma free fatty acids (FFA) were analyzed by compartmental modelling. Both core and TG label distributed into an apparent volume 10-15% larger than the blood volume. Part of this probably represents margination to endothelial-binding-lipolysis sites. An open two-compartmental model for plasma FFA was derived from experiments where unesterified oleic acid complexed to albumin was injected. Applying this model revealed that most of the oleic acid from chylomicron triglycerides mixes with the FFA. The disappearance of chylomicron core label required a model in which the label transfers into a second compartment before it leaves the blood. The rate constant for the transformation was high and predicted that, on average, chylomicron spent less than 2 min in the first compartment. The rate out from the second compartment predicted that about 60% of the core label left blood while, on average, chylomicron retained more than half of its triglyceride molecules, i.e., after rather limited lipolysis. The mechanism by which the core label leaves blood is not clear. Modelling showed that under the assumption that the process is shared by chylomicron triglycerides, about half of them go out by this pathway. Comparing fed and fasted rats, the main differences were in the turnover of FFA and in the extent to which chylomicron TG label reappeared in the FFA. This study indicates that a large fraction of the triglycerides in chylomicrons leave plasma together with the core lipids and that most of the fatty acids from chylomicron triglycerides mix into the same metabolic compartments as do plasma free fatty acids.

  • 50.
    Hultin, Magnus
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Anestesiologi och intensivvård.
    Savonen, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Chevreuil, Olivier
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Olivecrona, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Chylomicron metabolism in rats: kinetic modeling indicates that the particles remain at endothelial sites for minutes2013Inngår i: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 54, nr 10, 2595-2605 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chylomicrons labeled in vivo with (14)C-oleic acid (primarily in triglycerides, providing a tracer for lipolysis) and (3)H-retinol (primarily in ester form, providing a tracer for the core lipids) were injected into rats. Radioactivity in tissues was followed at a series of times up to 40 min and the data were analyzed by compartmental modeling. For heart-like tissues it was necessary to allow the chylomicrons to enter into a compartment where lipolysis is rapid and then transfer to a second compartment where lipolysis is slower. The particles remained in these compartments for minutes and when they returned to blood they had reduced affinity for binding in the tissue. In contrast, the data for liver could readily be fitted with a single compartment for native and lipolyzed chylomicrons in blood, and there was no need for a pathway back to blood. A composite model was built from the individual tissue models. This whole-body model could simultaneously fit all data for both fed and fasted rats and allowed estimation of fluxes and residence times in the four compartments; native and lipolyzed chylomicrons ("remnants") in blood, and particles in the tissue compartments where lipolysis is rapid and slow, respectively.

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