Browsing by Subject "CHOLESTEROL"

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  • Vojinovic, Dina; Kalaoja, Marita; Trompet, Stella; Fischer, Krista; Shipley, Martin J.; Li, Shuo; Havulinna, Aki S.; Perola, Markus; Salomaa, Veikko; Yang, Qiong; Sattar, Naveed; Jousilahti, Pekka; Amin, Najaf; Satizabal, Claudia L.; Taba, Nele; Sabayan, Behnam; Vasan, Ramachandran S.; Ikram, M. Arfan; Stott, David J.; Ala-Korpela, Mika; Jukema, J. Wouter; Seshadri, Sudha; Kettunen, Johannes; Kivimaki, Mika; Esko, Tonu; van Duijn, Cornelia M. (2021)
    Objective To conduct a comprehensive analysis of circulating metabolites and incident stroke in large prospective population-based settings. Methods We investigated the association of metabolites with risk of stroke in 7 prospective cohort studies including 1,791 incident stroke events among 38,797 participants in whom circulating metabolites were measured by nuclear magnetic resonance technology. The relationship between metabolites and stroke was assessed with Cox proportional hazards regression models. The analyses were performed considering all incident stroke events and ischemic and hemorrhagic events separately. Results The analyses revealed 10 significant metabolite associations. Amino acid histidine (hazard ratio [HR] per SD 0.90, 95% confidence interval [CI] 0.85, 0.94; p = 4.45 x 10-5), glycolysis-related metabolite pyruvate (HR per SD 1.09, 95% CI 1.04, 1.14; p = 7.45 x 10-4), acute-phase reaction marker glycoprotein acetyls (HR per SD 1.09, 95% CI 1.03, 1.15; p = 1.27 x 10-3), cholesterol in high-density lipoprotein (HDL) 2, and several other lipoprotein particles were associated with risk of stroke. When focused on incident ischemic stroke, a significant association was observed with phenylalanine (HR per SD 1.12, 95% CI 1.05, 1.19; p = 4.13 x 10-4) and total and free cholesterol in large HDL particles. Conclusions We found association of amino acids, glycolysis-related metabolites, acute-phase reaction markers, and several lipoprotein subfractions with the risk of stroke. These findings support the potential of metabolomics to provide new insights into the metabolic changes preceding stroke.
  • Poojari, Chetan; Wilkosz, Natalia; Lira, Rafael B.; Dimova, Rumiana; Jurkiewicz, Piotr; Petka, Rafal; Kepczynski, Mariusz; Rog, Tomasz (2019)
    1,6-Diphenyl-1,3,5-hexatriene (DPH) is one of the most commonly used fluorescent probes to study dynamical and structural properties of lipid bilayers and cellular membranes via measuring steady-state or time-resolved fluorescence anisotropy. In this study, we present a limitation in the use of DPH to predict the order of lipid acyl chains when the lipid bilayer is doped with itraconazole (ITZ), an antifungal drug. Our steady-state fluorescence anisotropy measurements showed a significant decrease in fluorescence anisotropy of DPH embedded in the ITZ-containing membrane, suggesting a substantial increase in membrane fluidity, which indirectly indicates a decrease in the order of the hydrocarbon chains. This result or its interpretation is in disagreement with the fluorescence recovery after photobleaching measurements and molecular dynamics (MD) simulation data. The results of these experiments and calculations indicate an increase in the hydrocarbon chain order. The MD simulations of the bilayer containing both ITZ and DPH provide explanations for these observations. Apparently, in the presence of the drug, the DPH molecules are pushed deeper into the hydrophobic membrane core below the lipid double bonds, and the probe predominately adopts the orientation of the ITZ molecules that is parallel to the membrane surface, instead of orienting parallel to the lipid acyl chains. For this reason, DPH anisotropy provides information related to the less ordered central region of the membrane rather than reporting the properties of the upper segments of the lipid acyl chains.
  • Liang, Yajun; Ngandu, Tiia; Laatikainen, Tiina; Soininen, Hilkka; Tuomilehto, Jaakko; Kivipelto, Miia; Qiu, Chengxuan (2020)
    Background Very few studies have explored the patterns of cardiovascular health (CVH) metrics in midlife and late life in relation to risk of dementia. We examined the associations of composite CVH metrics from midlife to late life with risk of incident dementia. Methods and findings This cohort study included 1,449 participants from the Finnish Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study, who were followed from midlife (baseline from1972 to 1987; mean age 50.4 years; 62.1% female) to late life (1998), and then 744 dementia-free survivors were followed further into late life (2005 to 2008). We defined and scored global CVH metrics based on 6 of the 7 components (i.e., smoking, physical activity, and body mass index [BMI] as behavioral CVH metrics; fasting plasma glucose, total cholesterol, and blood pressure as biological CVH metrics) following the modified American Heart Association (AHA)'s recommendations. Then, the composite global, behavioral, and biological CVH metrics were categorized into poor, intermediate, and ideal levels. Dementia was diagnosed following the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. Data were analyzed with Cox proportional hazards and the Fine and Gray competing risk regression models. During the follow-up examinations, dementia was diagnosed in 61 persons in 1998 and additional 47 persons in 2005 to 2008. The fully adjusted hazard ratio (HR) of dementia was 0.71 (95% confidence interval [CI]: 0.43, 1.16; p = 0.174) and 0.52 (0.29, 0.93; p = 0.027) for midlife intermediate and ideal levels (versus poor level) of global CVH metrics, respectively; the corresponding figures for late-life global CVH metrics were 0.60 (0.22, 1.69; p = 0.338) and 0.91 (0.34, 2.41; p = 0.850). Compared with poor global CVH metrics in both midlife and late life, the fully adjusted HR of dementia was 0.25 (95% CI: 0.08, 0.86; p = 0.028) for people with intermediate global CVH metrics in both midlife and late life and 0.14 (0.02, 0.76; p = 0.024) for those with midlife ideal and late-life intermediate global CVH metrics. Having an intermediate or ideal level of behavioral CVH in both midlife and late life (versus poor level in both midlife and late life) was significantly associated with a lower dementia risk (HR range: 0.03 to 0.26; p <0.05), whereas people with midlife intermediate and late-life ideal biological CVH metrics had a significantly increased risk of dementia (p = 0.031). Major limitations of this study include the lack of data on diet and midlife plasma glucose, high rate of attrition, as well as the limited power for certain subgroup analyses. Conclusions In this study, we observed that having the ideal CVH metrics, and ideal behavioral CVH metrics in particular, from midlife onwards is associated with a reduced risk of dementia as compared with people having poor CVH metrics. Maintaining life-long health behaviors may be crucial to reduce late-life risk of dementia. Author summary Why was this study done? Dementia is a global public health problem, but there is currently no cure or a disease-modifying therapy for dementia. Simulation studies suggested that interventions targeting modifiable risk factors (e.g., cardiovascular factors) could prevent up to one-third of dementia cases. A better understanding of the life-long cardiovascular health (CVH) metrics and risk of dementia may facilitate the development of optimal intervention strategies. What did the researchers do and find? We examined the associations of CVH metrics in midlife and late life with risk of incident dementia in a population-based cohort of 1,449 participants in Finland followed for around 30 years. Compared with poor CVH metrics, the ideal global and behavioral CVH metrics in midlife were associated with a reduced risk of dementia, whereas the ideal biological CVH metrics in late life appeared to be associated with an increased risk of dementia. Having an intermediate or ideal level of behavioral CVH metrics from midlife onwards was associated with a late-life reduced risk of dementia. What do these findings mean? The association of ideal global CVH metrics with a reduced dementia risk disappeared from midlife to old age, driven largely by the age-varying association between biological CVH metrics and risk of dementia. Maintaining a life-long optimal level of CVH metrics, especially behavioral health metrics, may reduce late-life risk of dementia. The association of late-life ideal biological CVH metrics with an increased risk of dementia may largely reflect the potential of reverse causality.
  • Rovio, Suvi P.; Pahkala, Katja; Nevalainen, Jaakko; Juonala, Markus; Salo, Pia; Kahonen, Mika; Hutri-Kahonen, Nina; Lehtimaki, Terho; Jokinen, Eero; Laitinen, Tomi; Taittonen, Leena; Tossavainen, Paivi; Viikari, Jorma S. A.; Rinne, Juha O.; Raitakari, Olli T. (2017)
    BACKGROUND In adults, high blood pressure (BP), adverse serum lipids, and smoking associate with cognitive deficits. The effects of these risk factors from childhood on midlife cognitive performance are unknown. OBJECTIVES This study sought to investigate the associations between childhood/adolescence cardiovascular risk factors and midlife cognitive performance. METHODS From 1980, a population-based cohort of 3,596 children (baseline age: 3 to 18 years) have been followed for 31 years in 3- to 9-year intervals. BP, serum lipids, body mass index, and smoking were assessed in all follow-ups. Cumulative exposure as the area under the curve for each risk factor was determined in childhood (6 to 12 years), adolescence (12 to 18 years), and young adulthood (18 to 24 years). In 2011, cognitive testing was performed in 2,026 participants aged 34 to 49 years. RESULTS High systolic BP, elevated serum total-cholesterol, and smoking from childhood were independently associated with worse midlife cognitive performance, especially memory and learning. The number of early life risk factors, including high levels (extreme 75th percentile for cumulative risk exposure between ages 6 and 24 years) of systolic BP, total-cholesterol, and smoking associated inversely with midlife visual and episodic memory and visuospatial associative learning (-0.140 standard deviations per risk factor, p <0.0001) and remained significant after adjustment for contemporaneous risk factors. Individuals with all risk factors within recommended levels between ages 6 and 24 years performed 0.29 standard deviations better (p = 0.006) on this cognitive domain than those exceeding all risk factor guidelines at least twice. This difference corresponds to the effect of 6 years aging on this cognitive domain. CONCLUSIONS Cumulative burden of cardiovascular risk factors from childhood/adolescence associate with worse midlife cognitive performance independent of adulthood exposure. (C) 2017 by the American College of Cardiology Foundation.
  • Pham, Dan Duc; Bruelle, Celine; Do, Hai Thi; Pajanoja, Ceren; Jin, Congyu; Olkkonen, Vesa M.; Eriksson-Rosenberg, Ove; Jauhiainen, Matti; Lalowski, Maciej; Lindholm, Dan (2019)
    Lipid-induced toxicity is part of several human diseases, but the mechanisms involved are not fully understood. Fatty liver is characterized by the expression of different growth and tissue factors. The neurotrophin, nerve growth factor (NGF) and its pro-form, pro-NGF, are present in fatty liver together with p75 neurotrophin receptor (p75NTR). Stimulation of human Huh7 hepatocyte cells with NGF and pro-NGF induced Sterol-regulator-element-binding protein-2 (SREBP2) activation and increased Low-Density Lipoprotein Receptor (LDLR) expression. We observed that phosphorylation of caspase-2 by p38 MAPK was essential for this regulation involving a caspase-3-mediated cleavage of SREBP2. RNA sequencing showed that several genes involved in lipid metabolism were altered in p75NTR-deficient mouse liver. The same lipogenic genes were downregulated in p75NTR gene-engineered human Huh7 cells and reciprocally upregulated by stimulation of p75NTRs. In the knock-out mice the serum cholesterol and triglyceride levels were reduced, suggesting a physiological role of p75NTRs in whole-body lipid metabolism. Taken together, this study shows that p75NTR signaling influences a network of genes involved in lipid metabolism in liver and hepatocyte cells. Modulation of p75NTR signaling may be a target to consider in various metabolic disorders accompanied by increased lipid accumulation.
  • Holm, Matilda; Saraswat, Mayank; Joenväärä, Sakari; Ristimäki, Ari; Haglund, Caj; Renkonen, Risto (2018)
    Over 1.4 million people are diagnosed with colorectal cancer (CRC) each year, making it the third most common cancer in the world. Increased screening and therapeutic modalities including improved combination treatments have reduced CRC mortality, although incidence and mortality rates are still increasing in some areas. Serum-based biomarkers are mainly used for follow-up of cancer, and are ideal due to the ease and minimally invasive nature of sample collection. Unfortunately, CEA and other serum markers have too low sensitivity for screening and preoperative diagnostic purposes. Increasing interest is focused on the possible use of biomarkers for predicting treatment response and prognosis in cancer. In this study, we have performed mass spectrometry analysis (UPLC-UDMSE) of serum samples from 19 CRC patients. Increased levels of C-reactive protein (CRP), which occur during local inflammation and the presence of a systemic inflammatory response, have been linked to poor prognosis in CRC patients. We chose to analyze samples according to CRP values by dividing them into the categories CRP 30, and, separately, according to short and long 5-year survival. The aim was to discover differentially expressed proteins associated with poor prognosis and shorter survival. We quantified 256 proteins and performed detailed statistical analyses and pathway analysis. We discovered multiple proteins that are up- or downregulated in patients with CRP >30 as compared to CRP
  • Kulig, Waldemar; Korolainen, Hanna; Zatorska, Maria; Kwolek, Urszula; Wydro, Pawel; Kepczynski, Mariusz; Rog, Tomasz (2019)
    Phosphatidic acids (PAs) have many biological functions in biomembranes, e.g., they are involved in the proliferation, differentiation, and transformation of cells. Despite decades of research, the molecular understanding of how PAs affect the properties of biomembranes remains elusive. In this study, we explored the properties of lipid bilayers and monolayers composed of PAs and phosphatidylcholines (PCs) with various acyl chains. For this purpose, the Langmuir monolayer technique and atomistic molecular dynamics (MD) simulations were used to study the miscibility of PA and PC lipids and the molecular organization of mixed bilayers. The monolayer experiments demonstrated that the miscibility of membrane components strongly depends on the structure of the hydrocarbon chains and thus on the overall lipid shape. Interactions between PA and PC molecules vary from repulsive, for systems containing lipids with saturated and unsaturated acyl tails (strongly positive values of the excess free energy of mixing), to attractive, for systems in which all lipid tails are saturated (negative values of the excess free energy of mixing). The MD simulations provided atomistic insight into polar interactions (formation of hydrogen bonds and charge pairs) in PC-PA systems. H-bonding between PA monoanions and PCs in mixed bilayers is infrequent, and the lipid molecules interact mainly via electrostatic interactions. However, the number of charge pairs significantly decreases with the number of unsaturated lipid chains in the PA-PC system. The PA dianions weakly interact with the zwitterionic lipids, but their headgroups are more hydrated as compared to the monoanionic form. The acyl chains in all PC-PA bilayers are more ordered compared to single-component PC systems. In addition, depending on the combination of lipids, we observed a deeper location of the PA phosphate groups compared to the PC phosphate groups, which can alter the presentation of PAs for the peripheral membrane proteins, affecting their accessibility for binding.
  • Stepien, Piotr; Augustyn, Bozena; Poojari, Chetan; Galan, Wojciech; Polit, Agnieszka; Vattulainen, Ilpo; Wisnieska-Becker, Anna; Rog, Tomasz (2020)
    Lipid nanodiscs are macromolecular assemblies, where a scaffold protein is wrapped around a nanosized disc of a lipid bilayer, thus protecting the hydrocarbon chains at the disc edges from unfavorable interactions with water. These nanostructures have numerous applications in, e.g., nanotechnology and pharmaceutics, and in investigations of membrane proteins. Here, we present results based on atomistic molecular dynamics simulations combined with electron paramagnetic spectroscopy measurements on the structure and dynamics of lipids in single-component nanodiscs. Our data highlight the existence of three distinctly different lipid fractions: central lipids residing in the center of a nanodisc, boundary lipids in direct contact with a scaffold protein, and intermediate lipids between these two regions. The central lipids are highly ordered and characterized by slow diffusion. In this part of the nanodisc, the membrane is the thickest and characterized by a gel-like or liquid-ordered phase, having features common to cholesterol-rich membranes. The boundary lipids in direct contact with the scaffold protein turned out to be less ordered and characterized by faster diffusion, and they remained in the liquid-disordered phase even at temperatures that were somewhat below the main phase transition temperature (Tm). The enthalpies associated with the central-boundary and central-intermediate transitions were similar to those observed for lipids going through the main phase transition. Overall, the study reveals lipid nanodiscs to be characterized by a complex internal structure, which is expected to influence membrane proteins placed in nanodiscs.
  • Latorre, Jèssica; Ortega, Francisco J.; Liñares-Pose, Laura; Moreno-Navarrete, José M.; Lluch, Aina; Comas, Ferran; Oliveras-Cañellas, Núria; Ricart, Wifredo; Höring, Marcus; Zhou, You; Liebisch, Gerhard; Nidhina Haridas, P.A.; Olkkonen, Vesa M.; López, Miguel; Fernández-Real, José M. (2020)
    Background: While the impact of metformin in hepatocytes leads to fatty acid (FA) oxidation and decreased lipogenesis, hepatic microRNAs (miRNAs) have been associated with fat overload and impaired metabolism, contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Methods: We investigated the expression of hundreds of miRNAs in primary hepatocytes challenged by compounds modulating steatosis, palmitic acid and compound C (as inducers), and metformin (as an inhibitor). Then, additional hepatocyte and rodent models were evaluated, together with transient mimic miRNAs transfection, lipid droplet staining, thin-layer chromatography, quantitative lipidomes, and mitochondrial activity, while human samples outlined the translational significance of this work. Findings: Our results show that treatments triggering fat accumulation and AMPK disruption may compromise the biosynthesis of hepatic miRNAs, while the knockdown of the miRNA-processing enzyme DICER in human hepatocytes exhibited increased lipid deposition. In this context, the ectopic recovery of miR-30b and miR-30c led to significant changes in genes related to FA metabolism, consistent reduction of ceramides, higher mitochondrial activity, and enabled b-oxidation, redirecting FA metabolism fromenergy storage to expenditure. Interpretation: Current findings unravel the biosynthesis of hepatic miR-30b and miR-30c in tackling inadequate FA accumulation, offering a potential avenue for the treatment of NAFLD. Funding: Instituto de Salud Carlos III (ISCIII), Govern de la Generalitat (PERIS2016), Associacio Catalana de Diabetis (ACD), Sociedad Espanola de Diabetes (SED), Fondo Europeo de Desarrollo Regional (FEDER), Xunta de Galicia, Ministerio de Economia y Competitividad (MINECO), "La Caixa" Foundation, and CIBER de la Fisiopatologia de la Obesidad y Nutricion (CIBEROBN). (c) 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)
  • Key, Timothy J.; Appleby, Paul N.; Bradbury, Kathryn E.; Sweeting, Michael; Wood, Angela; Johansson, Ingegerd; Kuehn, Tilman; Steur, Marinka; Weiderpass, Elisabete; Wennberg, Maria; Wuertz, Anne Mette Lund; Agudo, Antonio; Andersson, Jonas; Arriola, Larraitz; Boeing, Heiner; Boer, Jolanda M. A.; Bonnet, Fabrice; Boutron-Ruault, Marie-Christine; Cross, Amanda J.; Ericson, Ulrika; Fagherazzi, Guy; Ferrari, Pietro; Gunter, Marc; Huerta, Jose Maria; Katzke, Verena; Khaw, Kay-Tee; Krogh, Vittorio; La Vecchia, Carlo; Matullo, Giuseppe; Moreno-Iribas, Conchi; Naska, Androniki; Nilsson, Lena Maria; Olsen, Anja; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Molina-Portillo, Elena; Quiros, J. Ramon; Skeie, Guri; Sluijs, Ivonne; Sonestedt, Emily; Stepien, Magdalena; Tjonneland, Anne; Trichopoulou, Antonia; Tumino, Rosario; Tzoulaki, Ioanna; van der Schouw, Yvonne T.; Verschuren, W. M. Monique; di Angelantonio, Emanuele; Langenberg, Claudia; Forouhi, Nita; Wareham, Nick; Butterworth, Adam; Riboli, Elio; Danesh, John (2019)
    Background: There is uncertainty about the relevance of animal foods to the pathogenesis of ischemic heart disease (IHD). We examined meat, fish, dairy products, and eggs and risk for IHD in the pan-European EPIC cohort (European Prospective Investigation Into Cancer and Nutrition). Methods: In this prospective study of 409 885 men and women in 9 European countries, diet was assessed with validated questionnaires and calibrated with 24-hour recalls. Lipids and blood pressure were measured in a subsample. During a mean of 12.6 years of follow-up, 7198 participants had a myocardial infarction or died of IHD. The relationships of animal foods with risk were examined with Cox regression with adjustment for other animal foods and relevant covariates. Results: The hazard ratio (HR) for IHD was 1.19 (95% CI, 1.06-1.33) for a 100-g/d increment in intake of red and processed meat, and this remained significant after exclusion of the first 4 years of follow-up (HR, 1.25 [95% CI, 1.09-1.42]). Risk was inversely associated with intakes of yogurt (HR, 0.93 [95% CI, 0.89-0.98] per 100-g/d increment), cheese (HR, 0.92 [95% CI, 0.86-0.98] per 30-g/d increment), and eggs (HR, 0.93 [95% CI, 0.88-0.99] per 20-g/d increment); the associations with yogurt and eggs were attenuated and nonsignificant after exclusion of the first 4 years of follow-up. Risk was not significantly associated with intakes of poultry, fish, or milk. In analyses modeling dietary substitutions, replacement of 100 kcal/d from red and processed meat with 100 kcal/d from fatty fish, yogurt, cheese, or eggs was associated with approximate to 20% lower risk of IHD. Consumption of red and processed meat was positively associated with serum non-high-density lipoprotein cholesterol concentration and systolic blood pressure, and consumption of cheese was inversely associated with serum non-high-density lipoprotein cholesterol. Conclusions: Risk for IHD was positively associated with consumption of red and processed meat and inversely associated with consumption of yogurt, cheese, and eggs, although the associations with yogurt and eggs may be influenced by reverse causation bias. It is not clear whether the associations with red and processed meat and cheese reflect causality, but they were consistent with the associations of these foods with plasma non-high-density lipoprotein cholesterol and for red and processed meat with systolic blood pressure, which could mediate such effects.
  • Ohukainen, Pauli; Kuusisto, Sanna; Kettunen, Johannes; Perola, Markus; Järvelin, Marjo-Riitta; Makinen, Ville-Petteri; Ala-Korpela, Mika (2020)
    Background and aims: Population subgrouping has been suggested as means to improve coronary heart disease (CHD) risk assessment. We explored here how unsupervised data-driven metabolic subgrouping, based on comprehensive lipoprotein subclass data, would work in large-scale population cohorts. Methods: We applied a self-organizing map (SOM) artificial intelligence methodology to define subgroups based on detailed lipoprotein profiles in a population-based cohort (n = 5789) and utilised the trained SOM in an independent cohort (n = 7607). We identified four SOM-based subgroups of individuals with distinct lipoprotein profiles and CHD risk and compared those to univariate subgrouping by apolipoprotein B quartiles. Results: The SOM-based subgroup with highest concentrations for non-HDL measures had the highest, and the subgroup with lowest concentrations, the lowest risk for CHD. However, apolipoprotein B quartiles produced better resolution of risk than the SOM-based subgroups and also striking dose-response behaviour. Conclusions: These results suggest that the majority of lipoprotein-mediated CHD risk is explained by apolipoprotein B-containing lipoprotein particles. Therefore, even advanced multivariate subgrouping, with comprehensive data on lipoprotein metabolism, may not advance CHD risk assessment
  • NHLBI TOPMED Lipids Working Grp (2018)
    Lipoprotein(a), Lp(a), is a modified low- density lipoprotein particle that contains apolipoprotein( a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans.
  • Karhu, Lasse; Magarkar, Aniket; Bunker, Alex; Xhaard, Henri (2019)
    We assess the stability of two previously suggested binding modes for the neuropeptide orexin-A in the OX2 receptor through extensive molecular dynamics simulations. As the activation determinants of the receptor remain unknown, we simulated an unliganded receptor and two small-molecular ligands, the antagonist suvorexant and the agonist Nag26 for comparison. Each system was simulated in pure POPC membrane as well as in the 25% cholesterol–POPC membrane. In total, we carried out 36 μs of simulations. Through this set of simulations, we report a stable binding mode for the C-terminus of orexin-A. In addition, we suggest interactions that would promote orexin receptor activation, as well as others that would stabilize the inactive state.
  • Kaurola, Petri; Sharma, Vivek; Vonk, Amanda; Vattulainen, Ilpo; Rog, Tomasz (2016)
    Quinone and its analogues (Q) constitute an important class of compounds that perform key electron transfer reactions in oxidative- and photo-phosphorylation. In the inner membrane of mitochondria, ubiquinone molecules undergo continuous redox transitions enabling electron transfer between the respiratory complexes. In such a dynamic system undergoing continuous turnover for ATP synthesis, an uninterrupted supply of substrate molecules is absolutely necessary. In the current work, we have performed atomistic molecular dynamics simulations and free energy calculations to assess the structure, dynamics, and localization of quinone and its analogues in a lipid bilayer, whose composition mimics the one in the inner mitochondrial membrane. The results show that there is a strong tendency of both quinone and quinol molecules to localize in the vicinity of the lipids' acyl groups, right under the lipid head group region. Additionally, we observe a second location in the middle of the bilayer where quinone molecules tend to stabilize. Translocation of quinone through a lipid bilayer is very fast and occurs in 10-100 ns time scale, whereas the translocation of quinol is at least an order of magnitude slower. We suggest that this has important mechanistic implications given that the localization of Q ensures maximal occupancy of the Q-binding sites or Q-entry points in electron transport chain complexes, thereby maintaining an optimal turnover rate for ATP synthesis. (C) 2016 Elsevier B.V. All rights reserved.
  • Danne, Reinis; Poojari, Chetan; Martinez-Seara, Hector; Rissanen, Sami; Lolicato, Fabio; Rog, Tomasz; Vattulainen, Ilpo (2017)
    Carbohydrates constitute a structurally and functionally diverse group of biological molecules and macromolecules. In cells they are involved in, e.g., energy storage, signaling, and cellcell recognition. All of these phenomena take place in atomistic scales, thus atomistic simulation would be the method of choice to explore how carbohydrates function. However, the progress in the field is limited by the lack of appropriate tools for preparing carbohydrate structures and related topology files for the simulation models. Here we present tools that fill this gap. Applications where the tools discussed in this paper are particularly useful include, among others, the preparation of structures for glycolipids, nanocellulose, and glycans linked to glycoproteins. The molecular structures and simulation files generated by the tools are compatible with GROMACS.
  • Lamichhane, Santosh; Ahonen, Linda; Dyrlund, Thomas Sparholt; Kemppainen, Esko; Siljander, Heli; Hyoty, Heikki; Ilonen, Jorma; Toppari, Jorma; Veijola, Riitta; Hyotylainen, Tuulia; Knip, Mikael; Oresic, Matej (2018)
    Type 1 diabetes (T1D) is one of the most prevalent autoimmune diseases among children in Western countries. Earlier metabolomics studies suggest that T1D is preceded by dysregulation of lipid metabolism. Here we used a lipidomics approach to analyze molecular lipids in a prospective series of 428 plasma samples from 40 children who progressed to T1D (PT1D), 40 children who developed at least a single islet autoantibody but did not progress to T1D during the follow-up (P1Ab) and 40 matched controls (CTR). Sphingomyelins were found to be persistently downregulated in PT1D when compared to the P1Ab and CTR groups. Triacylglycerols and phosphatidylcholines were mainly downregulated in PT1D as compared to P1Ab at the age of 3 months. Our study suggests that distinct lipidomic signatures characterize children who progressed to islet autoimmunity or overt T1D, which may be helpful in the identification of at-risk children before the initiation of autoimmunity.
  • Shuhei, Nakanishi; Söderlund, Sanni; Jauhiainen, Matti; Taskinen, Marja-Riitta (2010)
  • Baumgartner, Sabine; Mensink, Ronald P.; De Smet, Els; Konings, Maurice; Fuentes, Susana; de Vos, Willem M.; Plat, Jogchum (2017)
    Information regarding dietary effects on plasma oxyphytosterol concentrations as well as on the origin of oxyphytosterols is scarce. We hypothesized that plant sterols are oxidized in the intestinal lumen, mediated by microbial activity, followed by uptake into the circulation. To address this hypothesis, we carried out, a randomized, double blind, crossover study in 13 healthy subjects, who consumed for 3 weeks control and plant stanol ester enriched margarines (3.0 g/d plant stanols) separated by a 4-week wash-out period. Plasma oxy(phyto)sterols were determined via GC-MS/MS, while microbiota analyses were performed on fecal DNA using a phylogenetic microarray to assess microbial composition and diversity. Plasma plant sterol concentrations did not correlate with plasma oxyphytosterols concentrations at baseline. Plant stanol consumption reduced serum sitosterol and campesterol concentrations (-37% and -38%), respectively (p <0.001), as well as plasma concentrations of 7 beta-OH-campesterol (-24%; p <0.05), 7 beta-OH-sitosterol (-17%; p <0.05) and 7-keto-sitosterol (-13%; p <0.05). Although the intestinal microbiota composition and diversity of the faecal contents were not different between the two periods, we observed significant correlations between several specific bacterial groups and plasma plant sterol, but not with plasma oxyphytosterol concentrations. In conclusion, plant stanol ester consumption reduced serum plant sterol and plasma oxyphytosterol concentrations, while intestinal microbiota composition and diversity were not changed. To definitely answer the effects of microbiota on oxyphytosterol formation, future studies could examine oxyphytosterol concentrations after changing intestinal microbial composition or by measuring intestinal oxyphytosterol formation after providing labelled non-oxidized plant sterols. (C) 2016 Elsevier Ltd. All rights reserved.