Browsing by Subject "VLDL"

Sort by: Order: Results:

Now showing items 1-7 of 7
  • Tynkkynen, Juho; Chouraki, Vincent; van der Lee, Sven J.; Hernesniemi, Jussi; Yang, Qiong; Li, Shuo; Beiser, Alexa; Larson, Martin G.; Sääksjärvi, Katri; Shipley, Martin J.; Singh-Manoux, Archana; Gerszten, Robert E.; Wang, Thomas J.; Havulinna, Aki S.; Würtz, Peter; Fischer, Krista; Demirkan, Ayse; Ikram, M. Arfan; Amin, Najaf; Lehtimäki, Terho; Kähönen, Mika; Perola, Markus; Metspalu, Andres; Kangas, Antti J.; Soininen, Pasi; Ala-Korpela, Mika; Vasan, Ramachandran S.; Kivimäki, Mika; van Duijn, Cornelia M.; Seshadri, Sudha; Salomaa, Veikko (2018)
    Introduction: Metabolite, lipid, and lipoprotein lipid profiling can provide novel insights into mechanisms underlying incident dementia and Alzheimer's disease. Methods: We studied eight prospective cohorts with 22,623 participants profiled by nuclear magnetic resonance or mass spectrometry metabolomics. Four cohorts were used for discovery with replication undertaken in the other four to avoid false positives. For metabolites that survived replication, combined association results are presented. Results: Over 246,698 person-years, 995 and 745 cases of incident dementia and Alzheimer's disease were detected, respectively. Three branched-chain amino acids (isoleucine, leucine, and valine), creatinine and two very low density lipoprotein (VLDL)-specific lipoprotein lipid subclasses were associated with lower dementia risk. One high density lipoprotein (HDL; the concentration of cholesterol esters relative to total lipids in large HDL) and one VLDL (total cholesterol to total lipids ratio in very large VLDL) lipoprotein lipid subclass was associated with increased dementia risk. Branched-chain amino acids were also associated with decreased Alzheimer's disease risk and the concentration of cholesterol esters relative to total lipids in large HDL with increased Alzheimer's disease risk. Discussion: Further studies can clarify whether these molecules play a causal role in dementia pathogenesis or are merely markers of early pathology. (C) 2018 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.
  • Packard, Chris J.; Boren, Jan; Taskinen, Marja-Riitta (2020)
    Elevations in plasma triglyceride are the result of overproduction and impaired clearance of triglyceride-rich lipoproteins-very low-density lipoproteins (VLDL) and chylomicrons. Hypertriglyceridemia is characterized by an accumulation in the circulation of large VLDL-VLDL1-and its lipolytic products, and throughout the VLDL-LDL delipidation cascade perturbations occur that give rise to increased concentrations of remnant lipoproteins and small, dense low-density lipoprotein (LDL). The elevated risk of atherosclerotic cardiovascular disease in hypertriglyceridemia is believed to result from the exposure of the artery wall to these aberrant lipoprotein species. Key regulators of the metabolism of triglyceride-rich lipoproteins have been identified and a number of these are targets for pharmacological intervention. However, a clear picture is yet to emerge as to how to relate triglyceride lowering to reduced risk of atherosclerosis.
  • Boren, Jan; Adiels, Martin; Bjornson, Elias; Matikainen, Niina; Söderlund, Sanni; Rämö, Joel; Ståhlman, Marcus; Ripatti, Pietari; Ripatti, Samuli; Palotie, Aarno; Mancina, Rosellina M.; Hakkarainen, Antti; Romeo, Stefano; Packard, Chris J.; Taskinen, Marja-Riitta (2020)
    Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation. The transmembrane 6 superfamily member 2 (TM6SF2) E167K genetic variant associates with NAFLD and with reduced plasma triglyceride levels in humans. However, the molecular mechanisms underlying these associations remain unclear. We hypothesized that TM65F2 E167K affects hepatic very low-density lipoprotein (VLDL) secretion and studied the kinetics of apolipoprotein 13100 (apoB100) and triglyceride metabolism in VLDL in homozygous subjects. In 10 homozygote TM6SF2 E167K carriers and 10 matched controls, we employed stable-isotope tracer and compartmental modeling techniques to determine apoB100 and triglyceride kinetics in the 2 major VIOL subtractions: large triglyceride-rich VLDL, and smaller, less triglyceride-rich VLDL2. VLDL1-apoB100 production was markedly reduced in homozygote TM6SF2 E167K carriers compared with controls. Likewise. VLDL,-triglyceride production was 35% lower in the TMSSF2 E167K carriers. In contrast, the direct production rates for VLDL2 apo13100 and triglyceride were not different between carriers and controls. In conclusion, the TM6SF2 E167K genetic variant was linked to a specific reduction in hepatic secretion of large triglyceride-rich VLDL1. The impaired secretion of VLDL1 explains the reduced plasma triglyceride concentration and provides a basis for understanding the lower risk of cardiovascular disease associated with the TM6SF2 E167K genetic variant.
  • Pervjakova, N.; Kukushkina, V.; Haller, T.; Kasela, S.; Joensuu, A.; Kristiansson, K.; Annilo, T.; Perola, M.; Salomaa, V.; Jousilahti, P.; Metspalu, A.; Magi, R. (2018)
    The aim of the study was to explore the parent-of-origin effects (POEs) on a range of human nuclear magnetic resonance metabolites. Materials & methods: We search for POEs in 14,815 unrelated individuals from Estonian and Finnish cohorts using POE method for the genotype data imputed with 1000 G reference panel and 82 nuclear magnetic resonance metabolites. Results: Meta-analysis revealed the evidence of POE for the variant rs1412727 in PTPRD gene for the metabolite: triglycerides in medium very low-density lipoprotein. No POEs were detected for genetic variants that were previously known to have main effect on circulating metabolites. Conclusion: We demonstrated possibility to detect POEs for human metabolites, but the POEs are weak, and therefore it is hard to detect those using currently available sample sizes.
  • Berglund, Martin; Adiels, Martin; Taskinen, Marja-Riitta; Boren, Jan; Wennberg, Bernt (2015)
    Context Mathematical models may help the analysis of biological systems by providing estimates of otherwise un-measurable quantities such as concentrations and fluxes. The variability in such systems makes it difficult to translate individual characteristics to group behavior. Mixed effects models offer a tool to simultaneously assess individual and population behavior from experimental data. Lipoproteins and plasma lipids are key mediators for cardiovascular disease in metabolic disorders such as diabetes mellitus type 2. By the use of mathematical models and tracer experiments fluxes and production rates of lipoproteins may be estimated. Results We developed a mixed effects model to study lipoprotein kinetics in a data set of 15 healthy individuals and 15 patients with type 2 diabetes. We compare the traditional and the mixed effects approach in terms of group estimates at various sample and data set sizes. Conclusion We conclude that the mixed effects approach provided better estimates using the full data set as well as with both sparse and truncated data sets. Sample size estimates showed that to compare lipoprotein secretion the mixed effects approach needed almost half the sample size as the traditional method.
  • Kemppainen, Aapeli (Helsingin yliopisto, 2019)
    Ateroskleroosi on maailmanlaajuisesti merkittävä, hitaasti kehittyvä suurten ja keskisuurten valtimoiden sairaus, jonka komplikaatiot aiheuttavat huomattavan määrän kuolemia ja sairaalahoidon tarvetta vuosittain. Sairautta on pidetty aikaisemmin aineenvaihdunnallisena tilana, jossa verisuonissa kiertävä kolesteroli kertyy verisuonen seinämään, mutta yhä enemmän ateroskleroosi mielletään tulehdukselliseksi sairaudeksi, jossa jatkuva matala-asteinen tulehdus on keskeinen tekijä taudin patogeneesissä. Nykyinen lääkehoito perustuu pitkälti hyperkolesterolemian hoitoon, mutta tulehdusta hoitamalla on myös onnistuttu vähentämään sydän- ja verisuonitapahtumia ja tulevaisuudessa tulehduksen lääkehoito voi korostua. Lipoproteiinien merkitystä ateroskleroosin patogeneesissä ei voida kiistää, sillä ilman sopivaa lipoproteiiniprofiilia (veressä) ei voi tautia kehittyä. Lipoproteiinit kantavat veressä lipidejä ja pääsevät verenkierrosta verisuonen seinämään. Seinämässä lipoproteiinit altistuvat monenlaiselle muuntumiselle. Monet hapettavat tekijät, fosfolipaasi, sfingomyelinaasi sekä muut entsyymit muokkaavat lipoproteiinien, ennen kaikkea LDL:n (low density lipoprotein), rakennetta, jolloin ne sitoutuvat helpommin verisuonen seinämässä solunulkoiseen tilaan, aggregoituvat sekä päätyvät makrofagien fagosytoimiksi. Epätasapaino lipoproteiinien kuljettamien lipidien virtauksessa verisuonen seinämään ja siitä pois johtaa lopulta lipidien kertymiseen. Makrofagit ovat tärkeitä soluja sekä verisuonen seinämän normaalissa aineenvaihdunnassa että ateroskleroosin kehittymisessä. Fagosytoituaan lipoproteiineja makrofagi prosessoi ne ja luovuttaa ylimääräisen kolesterolin eteenpäin. Kun kolesterolia kertyy soluun enemmän kuin mitä se pystyy luovuttamaan, muodostuu vaahtosoluja, jotka sisältävät ylimäärin kolesterolia ja muita lipidejä. Lipoproteiinien kertyessä makrofageihin, ne erittävät tulehdusta edistäviä välittäjäaineita. Endoteelisolut ovat toinen merkittävä solutyyppi verisuonen seinämässä. Ne säätelevät verisuonen läpäisevyyttä ja niihin vaikuttavat erityisesti muiden solujen erittämät välittäjäaineet. Myös lipoproteiineilla on suoria vaikutuksia endoteelisoluihin. Tässä tutkimuksessa altistettiin makrofageja ja endoteelisoluja luontaisille sekä muokatuille lipoproteiineille. Makrofagien osalta tavoitteena oli tutkia, miten lipoproteiinit vaikuttavat niiden interleukiinien (IL) eritykseen ja miten lipoproteiinien koko muuttuu altistuksen aikana. Endoteelisolujen kohdalla selvitettiin myös, miten lipoproteiinit vaikuttivat solujen geenien luentaan. Hapetetun VLDL:n (very-low density lipoprotein) todettiin aiheuttavan IL-1-erityksen makrofageista. Muilla muokatuilla lipoproteiineilla ei löydetty olevan tilastollisesti merkitsevää vaikutusta IL-1- tai IL-18- eritykseen. Endoteelisolut eivät erittäneet kyseisiä interleukiineja vuorokauden lipoproteiinialtistuksen jälkeen. Sekä makrofagit että endoteelisolut pienensivät VLDL:n ja hapetetun VLDL:n partikkelikokoa. LDL-partikkeleiden osalta makrofagit pienensivät lähinnä vain sfingomyelinaasilla muokatun LDL:n partikkelikokoa. Endoteelisolujen geenien luennassa ei havaittu muutosta endoteelisoluille ominaisista geeneistä mesenkymaalisoluille ominaisiin geeneihin, vaikka valomikroskoopilla nähtiin muutos endoteelisolujen morfologiassa.
  • Adiels, Martin; Taskinen, Marja-Riitta; Björnson, Elias; Andersson, Linda; Matikainen, Niina; Söderlund, Sanni; Kahri, Juhani; Hakkarainen, Antti; Lundbom, Nina; Sihlbom, Carina; Thorsell, Annika; Zhou, Haihong; Pietiläinen, Kirsi H.; Packard, Chris; Boren, Jan (2019)
    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-H-2(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.