Browsing by Subject "APOLIPOPROTEIN-B"

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  • Aminoff, Anna; Ledmyr, Helena; Thulin, Petra; Lundell, Kerstin; Nunez, Leyla; Strandhagen, Elisabeth; Murphy, Charlotte; Lidberg, Ulf; Westerbacka, Jukka; Franco-Cereceda, Anders; Liska, Jan; Nielsen, Lars Bo; Gafvels, Mats; Mannila, Maria Nastase; Hamsten, Anders; Yki-Järvinen, Hannele; Thelle, Dag; Eriksson, Per; Boren, Jan; Ehrenborg, Ewa (2010)
  • Nhlbi Trans-Omics Precision Med To; Natarajan, Pradeep; Pampana, Akhil; Graham, Sarah E.; Ruotsalainen, Sanni E.; Perry, James A.; de Vries, Paul S.; Broome, Jai G.; Palotie, Aarno; Ripatti, Samuli; Daly, Mark; Kaprio, Jaakko; Pulkki, Kari; Ripatti, Samuli; Kettunen, Johannes; Laaksonen, Reijo; Rinne, Juha; Pikkarainen, Sampsa; Eklund, Kari; Kauppi, Paula; Sinisalo, Juha; Taskinen, Marja-Riitta; Tuomi, Tiinamaija; Joensuu, Heikki; Meretoja, Tuomo; Aaltonen, Lauri; Turunen, Joni; Seitsonen, Sanna; Hannula-Jouppi, Katariina; Jalanko, Anu; Kajanne, Risto; Lyhs, Ulrike; Kaunisto, Mari; Kurki, Mitja; Karjalainen, Juha; Havulinna, Aki; Palta, Priit; Parolo, Pietro Della Briotta; Harju, Jarmo; Lehisto, Arto; Ganna, Andrea; Llorens, Vincent; Koskinen, Miika; Heikkinen, Sami; Loukola, Anu; Donner, Kati; Nunez-Fontarnau, Javier; Brein, Georg; Laivuori, Hannele; Kiiskinen, Tuomo (2021)
    Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P=8.5x10(-72)), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P=1.7x10(-4)), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P=1.4x10(-5)). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids. The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.
  • Maaninka, Katariina; Nguyen, Su Duy; Mäyränpää, Mikko I.; Plihtari, Riia; Rajamäki, Kristiina; Lindsberg, Perttu J.; Kovanen, Petri T.; Öörni, Katariina (2018)
    Background and aims: Subendothelial interaction of LDL with extracellular matrix drives atherogenesis. This interaction can be strengthened by proteolytic modification of LDL. Mast cells (MCs) are present in atherosclerotic lesions, and upon activation, they degranulate and release a variety of neutral proteases. Here we studied the ability of MC proteases to cleave apoB-100 of LDL and affect the binding of LDL to proteoglycans. Methods: Mature human MCs were differentiated from human peripheral blood-derived CD34(+) progenitors in vitro and activated with calcium ionophore to generate MC-conditioned medium. LDL was incubated in the MC-conditioned medium or with individual MC proteases, and the binding of native and modified LDL to isolated human aortic proteoglycans or to human atherosclerotic plaques ex vivo was determined. MC proteases in atherosclerotic human coronary artery lesions were detected by immunofluorescence and qPCR. Results: Activated human MCs released the neutral proteases tryptase, chymase, carboxypeptidase A3, cathepsin G, and granzyme B. Of these, cathepsin G degraded most efficiently apoB-100, induced LDL fusion, and enhanced binding of LDL to isolated human aortic proteoglycans and human atherosclerotic lesions ex vivo. Double immunofluoresence staining of human atherosclerotic coronary arteries for tryptase and cathepsin G indicated that lesional MCs contain cathepsin G. In the lesions, expression of cathepsin G correlated with the expression of tryptase and chymase, but not with that of neutrophil proteinase 3. Conclusions: The present study suggests that cathepsin G in human atherosclerotic lesions is largely derived from MCs and that activated MCs may contribute to atherogenesis by enhancing LDL retention. (C) 2018 Elsevier B.V. All rights reserved.
  • Luukkonen, Panu K.; Zhou, You; Haridas, Nidhina P. A.; Dwivedi, Om P.; Hyotylainen, Tuulia; Ali, Ashfaq; Juuti, Anne; Leivonen, Marja; Tukiainen, Taru; Ahonen, Linda; Scott, Emma; Palmer, Jeremy M.; Arola, Johanna; Orho-Melander, Marju; Vikman, Petter; Anstee, Quentin M.; Olkkonen, Vesa M.; Oresic, Matej; Groop, Leif; Yki-Jarvinen, Hannele (2017)
    Background: Carriers of the transmembrane 6 superfamily member 2 E167K gene variant (TM6SF2(EK/KK)) have decreased expression of the TM6SF2 gene and increased risk of NAFLD and NASH. Unlike common 'obese/metabolic' NAFLD, these subjects lack hypertriglyceridemia and have lower risk of cardiovascular disease. In animals, phosphatidylcholine (PC) deficiency results in a similar phenotype. PCs surround the core of VLDL consisting of triglycerides (TGs) and cholesteryl-esters (CEs). We determined the effect of the TM6SF2 E167K on these lipids in the human liver and serum and on hepatic gene expression and studied the effect of TM6SF2 knockdown on hepatocyte handling of these lipids. Methods: Liver biopsies were taken from subjects characterized with respect to the TM6SF2 genotype, serum and liver lipidome, gene expression and histology. In vitro, after TM6SF2 knockdown in HuH-7 cells, we compared incorporation of different fatty acids into TGs, CEs, and PCs. Results: The TM6SF2(EK/KK) and TM6SF2EE groups had similar age, gender, BMI and HOMA-IR. Liver TGs and CEs were higher and liver PCs lower in the TM6SF2(EK/KK) than the TM6SF2EE group (p Conclusions: Hepatic lipid synthesis from PUFAs is impaired and could contribute to deficiency in PCs and increased intrahepatic TG in TM6SF2 E167K variant carriers. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
  • Ruuth, Maija; Äikäs, Lauri; Tigistu-Sahle, Feven; Käkelä, Reijo; Lindholm, Harri; Simonen, Piia; Kovanen, Petri T.; Gylling, Helena; Öörni, Katariina (2020)
    OBJECTIVE: Plant stanol ester supplementation (2-3 g plant stanols/d) reduces plasma LDL (low-density lipoprotein) cholesterol concentration by 9% to 12% and is, therefore, recommended as part of prevention and treatment of atherosclerotic cardiovascular disease. In addition to plasma LDL-cholesterol concentration, also qualitative properties of LDL particles can influence atherogenesis. However, the effect of plant stanol ester consumption on the proatherogenic properties of LDL has not been studied. APPROACH AND RESULTS: Study subjects (n=90) were randomized to consume either a plant stanol ester-enriched spread (3.0 g plant stanols/d) or the same spread without added plant stanol esters for 6 months. Blood samples were taken at baseline and after the intervention. The aggregation susceptibility of LDL particles was analyzed by inducing aggregation of isolated LDL and following aggregate formation. LDL lipidome was determined by mass spectrometry. Binding of serum lipoproteins to proteoglycans was measured using a microtiter well-based assay. LDL aggregation susceptibility was decreased in the plant stanol ester group, and the median aggregate size after incubation for 2 hours decreased from 1490 to 620 nm,P=0.001. Plant stanol ester-induced decrease in LDL aggregation was more extensive in participants having body mass index CONCLUSIONS: Consumption of plant stanol esters decreases the aggregation susceptibility of LDL particles by modifying LDL lipidome. The resulting improvement of LDL quality may be beneficial for cardiovascular health. REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01315964. GRAPHIC ABSTRACT: A graphic abstract is available for this article.
  • Manninen, Suvi; Lankinen, Maria; Erkkilä, Arja; Nguyen, Su Duy; Ruuth, Maija; de Mello, Vanessa; Öörni, Katariina; Schwab, Ursula (2019)
    Background and aims: Omega-3 fatty acids are known to have several cardioprotective effects. Our aim was to investigate the effects of intakes of fish and Camelina sativa oil (CSO), rich in alpha-linolenic acid, on the atherogenic and anti-atherogenic functions of LDL and HDL particles. Methods: Altogether, 88 volunteers with impaired glucose metabolism were randomly assigned to CSO (10 g of alpha-linolenic acid/day), fatty fish (4 fish meals/week), lean fish (4 fish meals/week) or control group for 12 weeks. 79 subjects completed the study. The binding of lipoproteins to aortic proteoglycans, LDL aggregation and activation of endothelial cells by LDL and cholesterol efflux capacity of HDL were determined in vitro. Results: Intake of CSO decreased the binding of lipoproteins to aortic proteoglycans in a non-normalized model (p = 0.006). After normalizing with serum concentrations of non-HDL cholesterol, apolipoprotein B (apoB) or LDL cholesterol, which decreased in the CSO group, the change was no longer statistically significant. In the fish groups, there were no changes in the binding of lipoproteins to proteoglycans. Regarding other lipoprotein functions, there were no changes in any of the groups. Conclusions: Intake of CSO decreases the binding of lipoproteins to aortic proteoglycans by decreasing serum LDL cholesterol concentration, which suggests that the level of apoB-containing lipoproteins in the circulation is the main driver of lipoprotein retention within the arterial wall. Intake of fish or CSO has no effects on other lipoprotein functions.
  • Velagapudi, Vidya R.; Hezaveh, Rahil; Reigstad, Christopher S.; Gopalacharyulu, Peddinti; Yetukuri, Laxman; Islam, Sama; Felin, Jenny; Perkins, Rosie; Boren, Jan; Oresic, Matej; Backhed, Fredrik (2010)
  • Kumar, Vibhor; Butcher, Sarah J.; Öörni, Katariina; Engelhardt, Peter; Heikkonen, Jukka; Kaski, Kimmo; Ala-Korpela, Mika; Kovanen, Petri T. (2011)
    Background Low-density lipoprotein (LDL) particles, the major carriers of cholesterol in the human circulation, have a key role in cholesterol physiology and in the development of atherosclerosis. The most prominent structural components in LDL are the core-forming cholesteryl esters (CE) and the particle-encircling single copy of a huge, non-exchangeable protein, the apolipoprotein B-100 (apoB-100). The shape of native LDL particles and the conformation of native apoB-100 on the particles remain incompletely characterized at the physiological human body temperature (37°C). Methodology/Principal Findings To study native LDL particles, we applied cryo-electron microscopy to calculate 3D reconstructions of LDL particles in their hydrated state. Images of the particles vitrified at 6°C and 37°C resulted in reconstructions at ~16 Å resolution at both temperatures. 3D variance map analysis revealed rigid and flexible domains of lipids and apoB-100 at both temperatures. The reconstructions showed less variability at 6°C than at 37°C, which reflected increased order of the core CE molecules, rather than decreased mobility of the apoB-100. Compact molecular packing of the core and order in a lipid-binding domain of apoB-100 were observed at 6°C, but not at 37°C. At 37°C we were able to highlight features in the LDL particles that are not clearly separable in 3D maps at 6°C. Segmentation of apoB-100 density, fitting of lipovitellin X-ray structure, and antibody mapping, jointly revealed the approximate locations of the individual domains of apoB-100 on the surface of native LDL particles. Conclusions/Significance Our study provides molecular background for further understanding of the link between structure and function of native LDL particles at physiological body temperature.