135 results on '"Käkelä R"'
Search Results
2. Icosapent ethyl supplementation rapidly and transiently alters the composition and functionality of circulating lipoproteins in humans
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Äikäs, L., Hermansson, M., Holopainen, M., Ruhanen, H., Käkelä, R., Kovanen, P.T., and Öörni, K.
- Published
- 2022
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3. Fatty Acid Signatures in Seabird Plasma Are a Complex Function of Diet Composition: A Captive Feeding Trial with Herring Gulls
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Käkelä, R., Furness, R. W., Kahle, S., Becker, P. H., and Käkelä, A.
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- 2009
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4. Lysosomal dysfunction causes neurodegeneration in mucolipidosis II ‘knock-in’ mice
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Kollmann, K., Damme, M., Markmann, S., Morelle, W., Schweizer, M., Hermans-Borgmeyer, I., Röchert, A. K., Pohl, S., Lübke, T., Michalski, J.-C., Käkelä, R., Walkley, S. U., and Braulke, T.
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- 2012
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5. Streptococcus pneumoniae molecules convert high density lipoproteins into pro-atherogenic particles
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Syed, S., Nissilä, E., Ruhanen, H., Fudo, S., Gaytán, M.O., Sihvo, S.P., King, S.J., Metso, J., Oommen, O.P., Jauhiainen, M., Meri, S., Käkelä, R., and Haapasalo, K.
- Published
- 2021
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6. Lp(a) induces inflammasome activation in human macrophages
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Lorey, M.B., Borelli, M., Äikäs, L., Youssef, A., Hermansson, M., Kemppainen, A., Ruhanen, H., Ruuth, M., Matikainen, S., Kovanen, P.T., Käkelä, R., Boffa, M.B., Koschinsky, M.L., and Öörni, K.
- Published
- 2021
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7. Fatty acid alterations caused by PCBs (Aroclor 1242) and copper in adipose tissue around lymph nodes of mink
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Käkelä, R and Hyvärinen, H
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- 1999
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8. Lp(A)-Dependent Inflammasome Activation As A Driver Of Its Atherogenicity
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Öörni, K., Lorey, M.B., Borelli, M., Tigistu-Sahle, F., Ruuth, M., Äikäs, L., Käkelä, R., Boffa, M.B., and Koschinsky, M.L.
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- 2019
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9. ANGPTL3 knock-down alters hepatocyte lipid profile and metabolism
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Ruhanen, H., Nidhina Haridas, P.A., Zhou, Y., Jauhiainen, M., Käkelä, R., and Olkkonen, V.M.
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- 2018
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10. Susceptibility of LDL particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths
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Ruuth, M., Nguyen, S.D., Vihervaara, T., Hilvo, M., Uusitupa, M., Schwab, U., Savolainen, M., Jauhiainen, M., Käkelä, R., Baruch, A., Laaksonen, R., Kovanen, P.T., and Öörni, K.
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- 2018
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11. Has the income of the residential area impact on the use of intensive care?
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Liisanantti, J. H., Käkelä, R., Raatiniemi, L. V., Ohtonen, P., Hietanen, S., and Ala‐Kokko, T. I.
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INTENSIVE care units , *HOSPITAL admission & discharge , *RESIDENTIAL areas , *INCOME , *CATASTROPHIC illness , *SOCIOECONOMIC factors , *UNEMPLOYMENT , *ALCOHOLISM , *CRITICAL care medicine , *HOSPITAL care , *DISEASE incidence , *RETROSPECTIVE studies , *ECONOMICS - Abstract
Background: The socioeconomic factors have an impact on case mix and outcome in critical illness, but how these factors affect the use of intensive care is not studied. The aim of this study was to evaluate the incidence of intensive care unit (ICU) admissions in patients from residential areas with different annual incomes.Methods: Single-center, retrospective study in Northern Finland. All the non-trauma-related emergency admissions from the hospital district area were included. The postal codes were used to categorize the residential areas according to each area's annual median income: the low-income area, €18,979 to €28,841 per year; the middle-income area, €28,879 to €33,856 per year; and the high-income area, €34,221 to €53,864 per year.Results: A total of 735 non-trauma-related admissions were included. The unemployment or retirement, psychiatric comorbidities and chronic alcohol abuse were common in this population. The highest incidence, 5.5 (4.6-6.7)/1000/year, was in population aged more than 65 years living in high-income areas. In working-aged population, the incidence was lowest in high-income areas (1.5 (1.3-1.8/1000/year) compared to middle-income areas (2.2 (1.9-2.6)/1000/year, P = 0.001) and low-income areas (2.0 (1.7-2.4)/1000/, P = 0.009). Poisonings were more common in low-income areas. There were no differences in outcome.Conclusion: The incidence of ICU admission in working-aged population was 25% higher in those areas where the annual median income was below the median annual income of €38,775 per inhabitant per year in Finland. [ABSTRACT FROM AUTHOR]- Published
- 2017
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12. Unstable LDL – Novel mechanism of atherogenesis and link to cardiovascular deaths
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Ruuth, M., Nguyen, S.D., Vihervaara, T., Laajala, T.D., Uusitupa, M., Schwab, U., Savolainen, M., Sinisalo, J., Aittokallio, T., Käkelä, R., Jauhiainen, M., Kovanen, P., and Öörni, K.
- Published
- 2016
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13. Gill tissue lipids of salmon (Salmo salar L.) presmolts and smolts from anadromous and landlocked populations.
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Itokazu, Y., Käkelä, R., Piironen, J., Guan, X.L., Kiiskinen, P., and Vornanen, M.
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GILLS , *LIPIDS , *ATLANTIC salmon , *LECITHIN , *MASS spectrometry , *CHOLESTEROL , *ANATOMY - Abstract
Abstract: Composition of membrane lipids from the gills of juvenile Atlantic salmon (Salmo salar) in presmolt and smolt phases of development was compared among anadromous and non-anadromous populations. Three stocks migrating from spawning rivers to either lake (landlocked stock), brackish water or full strength sea water were grown under common garden conditions, and gill lipids and their acyl and alkenyl chains were examined in February (presmolts) and at the end of May (smolts) by mass spectrometry and gas–liquid chromatography. The most remarkable changes upon transition from the presmolt phase to the smolt phase were: (i) increase in the cholesterol/phospholipid ratio, (ii) decrease in the abundance of phosphatidylinositol (PI) content, (iii) increase in the amount of sulfatides, (iv) increase in phosphatidylcholine (PC) and phosphatidylethanolamine (PE) species with two highly unsaturated acyl chains, and finally (v) convergence of interstock differences in PC and PE species composition towards a similar lipid composition. Increases in the gill membrane content of cholesterol and sulfatides are discussed as pre-adaptation of salmon gills for salt-secretion, which may occur by increases in membrane microdomains (rafts) harboring ion channels and pumps. The decreases of PI were likely related to adjusting the gill membrane permeability to ions by diminishing prostanoid production. The similarity of those changes among three salmon stocks and the convergence of initially (presmolt phase) different PC and PE species profiles between the stocks towards similar lipid composition suggests that smoltification process of the gill epithelium is largely similar in anadromous and landlocked populations. [Copyright &y& Elsevier]
- Published
- 2014
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14. Abstract: P659 PROATHEROGENIC PATHOGENS REDUCE THE PUFA/SFA RATIO IN ADIPOSE TISSUES IN APOE-DEFICIENT MICE
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Hyvärinen, K, Tuomainen, A, Laitinen, S, Käkelä, R, Salminen, I, Alfthan, G, Jauhiainen, M, Kovanen, P, Leinonen, M, Saikku, P, and Pussinen, P
- Published
- 2009
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15. Mo-W15:5 Hepatic overexpression of oxysterol binding protein(OSBP) results in hypertriglyceridemia
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Yan, D., Lehto, M., Käkelä, R., Ylä-Herttuala, S., Ehnholm, C., Jauhiainen, M., and Olkkonen, V.M.
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- 2006
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16. Seasonal and genetic effects on lipid profiles of juvenile Atlantic salmon.
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House AH, Debes PV, Holopainen M, Käkelä R, Donner I, Frapin M, Ahi EP, Kurko J, Ruhanen H, and Primmer CR
- Abstract
Seasonality can influence many physiological traits requiring optimal energetic capacity for life-history stage transitions. In Atlantic salmon, high-energy status is essential for the initiation of maturation. Earlier studies have linked a genomic region encoding vgll3 to maturation age, potentially mediated via body condition. Vgll3 has also been shown to act as an inhibitor of adipogenesis in mice. Here we investigate the influence of season and vgll3 genotypes associating with early (EE) and late (LL) maturation on lipid profiles in the muscle and liver of juvenile Atlantic salmon. We reared Atlantic salmon for two years from fertilization and sampled muscle and liver during the spring and autumn of the second year (at which time some males were sexually mature). We found no seasonal or genotype effect in the muscle lipid profiles of immature males or females. However, in the liver we detected a triacylglycerol enrichment and a genotype specific direction of change in membrane lipids, phosphatidylcholine and phosphatidylethanolamine, from spring to autumn. Specifically, from spring to autumn membrane lipid concentrations increased in vgll3*EE individuals but decreased in vgll3*LL individuals. This could be explained by 1) a seasonally more stable capacity of endoplasmic reticulum (ER) functions in vgll3*EE individuals compared to vgll3*LL individuals or 2) vgll3*LL individuals storing larger lipid droplets from spring to autumn in the liver compared to vgll3*EE individuals at the expense of ER capacity. This genotype specific seasonal direction of change in membrane lipid concentrations provides more indirect evidence of a potential mechanism linking vgll3 with lipid metabolism and storage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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17. Increased secretion of adipocyte-derived extracellular vesicles is associated with adipose tissue inflammation and the mobilization of excess lipid in human obesity.
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Matilainen J, Berg V, Vaittinen M, Impola U, Mustonen AM, Männistö V, Malinen M, Luukkonen V, Rosso N, Turunen T, Käkelä P, Palmisano S, Arasu UT, Sihvo SP, Aaltonen N, Härkönen K, Caddeo A, Kaminska D, Pajukanta P, Kaikkonen MU, Tiribelli C, Käkelä R, Laitinen S, Pihlajamäki J, Nieminen P, and Rilla K
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- Humans, Lipid Metabolism, Female, Male, Adult, Fatty Acids metabolism, Extracellular Vesicles metabolism, Obesity metabolism, Obesity pathology, Adipocytes metabolism, Inflammation pathology, Inflammation metabolism, Adipose Tissue metabolism, Adipose Tissue pathology
- Abstract
Background: Obesity is a worldwide epidemic characterized by adipose tissue (AT) inflammation. AT is also a source of extracellular vesicles (EVs) that have recently been implicated in disorders related to metabolic syndrome. However, our understanding of mechanistic aspect of obesity's impact on EV secretion from human AT remains limited., Methods: We investigated EVs from human Simpson Golabi Behmel Syndrome (SGBS) adipocytes, and from AT as well as plasma of subjects undergoing bariatric surgery. SGBS cells were treated with TNFα, palmitic acid, and eicosapentaenoic acid. Various analyses, including nanoparticle tracking analysis, electron microscopy, high-resolution confocal microscopy, and gas chromatography-mass spectrometry, were utilized to study EVs. Plasma EVs were analyzed with imaging flow cytometry., Results: EVs from mature SGBS cells differed significantly in size and quantity compared to preadipocytes, disagreeing with previous findings in mouse adipocytes and indicating that adipogenesis promotes EV secretion in human adipocytes. Inflammatory stimuli also induced EV secretion, and altered EV fatty acid (FA) profiles more than those of cells, suggesting the role of EVs as rapid responders to metabolic shifts. Visceral AT (VAT) exhibited higher EV secretion compared to subcutaneous AT (SAT), with VAT EV counts positively correlating with plasma triacylglycerol (TAG) levels. Notably, the plasma EVs of subjects with obesity contained a higher number of adiponectin-positive EVs than those of lean subjects, further demonstrating higher AT EV secretion in obesity. Moreover, plasma EV counts of people with obesity positively correlated with body mass index and TNF expression in SAT, connecting increased EV secretion with AT expansion and inflammation. Finally, EVs from SGBS adipocytes and AT contained TAGs, and EV secretion increased despite signs of less active lipolytic pathways, indicating that AT EVs could be involved in the mobilization of excess lipids into circulation., Conclusions: We are the first to provide detailed FA profiles of human AT EVs. We report that AT EV secretion increases in human obesity, implicating their role in TAG transport and association with adverse metabolic parameters, thereby emphasizing their role in metabolic disorders. These findings promote our understanding of the roles that EVs play in human AT biology and metabolic disorders., (© 2024. The Author(s).)
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- 2024
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18. Lipid species profiling of bronchoalveolar lavage fluid cells of horses housed on two different bedding materials.
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Mönki J, Holopainen M, Ruhanen H, Karikoski N, Käkelä R, and Mykkänen A
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- Animals, Horses, Bronchoalveolar Lavage Fluid chemistry, Chromatography, Liquid, Prospective Studies, Soil, Phosphatidylinositols, Bedding and Linens, Bronchoalveolar Lavage, Tandem Mass Spectrometry, Inflammation veterinary
- Abstract
The lipidome of equine BALF cells has not been described. The objectives of this prospective repeated-measures study were to explore the BALF cells' lipidome in horses and to identify lipids associated with progression or resolution of airway inflammation. BALF cells from 22 horses exposed to two bedding materials (Peat 1-Wood shavings [WS]-Peat 2) were studied by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The effects of bedding on lipid class and species compositions were tested with rmANOVA. Correlations between lipids and cell counts were examined. The BALF cells' lipidome showed bedding-related differences for molar percentage (mol%) of 60 species. Whole phosphatidylcholine (PC) class and its species PC 32:0 (main molecular species 16:0_16:0) had higher mol% after Peat 2 compared with WS. Phosphatidylinositol 38:4 (main molecular species 18:0_20:4) was higher after WS compared with both peat periods. BALF cell count correlated positively with mol% of the lipid classes phosphatidylserine, sphingomyelin, ceramide, hexosylceramide, and triacylglycerol but negatively with PC. BALF cell count correlated positively with phosphatidylinositol 38:4 mol%. In conclusion, equine BALF cells' lipid profiles explored with MS-based lipidomics indicated subclinical inflammatory changes after WS. Inflammatory reactions in the cellular lipid species composition were detected although cytological responses indicating inflammation were weak., (© 2023. The Author(s).)
- Published
- 2023
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19. Systemwide effects of ER-intracellular membrane contact site disturbance in primary endothelial cells.
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Taskinen JH, Ruhanen H, Matysik S, Käkelä R, and Olkkonen VM
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- Humans, Human Umbilical Vein Endothelial Cells, Gene Knockdown Techniques, Metabolism, Neovascularization, Physiologic, Cholesterol metabolism, Esterification, Lipidomics, Protein Interaction Maps, Golgi Apparatus metabolism, Coat Protein Complex I metabolism, Endoplasmic Reticulum metabolism, Intracellular Membranes metabolism
- Abstract
Membrane contact sites (MCS) make up a crucial route of inter-organelle non-vesicular transport within the cell. Multiple proteins are involved in this process, which includes the ER-resident proteins vesicle associated membrane protein associated protein A and -B (VAPA/B) that form MCS between the ER and other membrane compartments. Currently most functional data on VAP depleted phenotypes have shown alterations in lipid homeostasis, induction of ER stress, dysfunction of UPR and autophagy, as well as neurodegeneration. Literature on concurrent silencing of VAPA/B is still sparse; therefore, we investigated how it affects the macromolecule pools of primary endothelial cells. Our transcriptomics results showed significant upregulation in genes related to inflammation, ER and Golgi dysfunction, ER stress, cell adhesion, as well as Coat Protein Complex-I and -II (COP-I, COP-II) vesicle transport. Genes related to cellular division were downregulated, as well as key genes of lipid and sterol biosynthesis. Lipidomics analyses revealed reductions in cholesteryl esters, very long chain highly unsaturated and saturated lipids, whereas increases in free cholesterol and relatively short chain unsaturated lipids were evident. Furthermore, the knockdown resulted in an inhibition of angiogenesis in vitro. We speculate that ER MCS depletion has led to multifaceted outcomes, which include elevated ER free cholesterol content and ER stress, alterations in lipid metabolism, ER-Golgi function and vesicle transport, which have led to a reduction in angiogenesis. The silencing also induced an inflammatory response, consistent with upregulation of markers of early atherogenesis. To conclude, ER MCS mediated by VAPA/B play a crucial role in maintaining cholesterol traffic and sustain normal endothelial functions., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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20. Increased n-6 Polyunsaturated Fatty Acids Indicate Pro- and Anti-Inflammatory Lipid Modifications in Synovial Membranes with Rheumatoid Arthritis.
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Mustonen AM, Tollis S, Käkelä R, Sihvo SP, Palosaari S, Pohjanen VM, Yli-Hallila A, Lehenkari P, and Nieminen P
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- Humans, Synovial Fluid chemistry, Synovial Membrane metabolism, Anti-Inflammatory Agents therapeutic use, Fatty Acids, Fatty Acids, Unsaturated metabolism, Arthritis, Rheumatoid metabolism, Osteoarthritis drug therapy
- Abstract
Emerging evidence suggests that fatty acids (FAs) and their lipid mediator derivatives can induce both beneficial and detrimental effects on inflammatory processes and joint degradation in osteoarthritis (OA) and autoimmune-driven rheumatoid arthritis (RA). The present study characterized the detailed FA signatures of synovial membranes collected during knee replacement surgery of age- and gender-matched OA and RA patients (n = 8/diagnosis). The FA composition of total lipids was determined by gas chromatography and analyzed with univariate and multivariate methods supplemented with hierarchical clustering (HC), random forest (RF)-based classification of FA signatures, and FA metabolism pathway analysis. RA synovium lipids were characterized by reduced proportions of shorter-chain saturated FAs (SFAs) and elevated percentages of longer-chain SFAs and monounsaturated FAs, alkenyl chains, and C20 n-6 polyunsaturated FAs compared to OA synovium lipids. In HC, FAs and FA-derived variables clustered into distinct groups, which preserved the discriminatory power of the individual variables in predicting the RA and OA inflammatory states. In RF classification, SFAs and 20:3n-6 were among the most important FAs distinguishing RA and OA. Pathway analysis suggested that elongation reactions of particular long-chain FAs would have increased relevance in RA. The present study was able to determine the individual FAs, FA groups, and pathways that distinguished the more inflammatory RA from OA. The findings suggest modifications of FA elongation and metabolism of 20:4n-6, glycerophospholipids, sphingolipids, and plasmalogens in the chronically inflamed RA synovium. These FA alterations could have implications in lipid mediator synthesis and potential as novel diagnostic and therapeutic tools., (© 2023. The Author(s).)
- Published
- 2023
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21. An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis.
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Talvio K, Wagner VA, Minkeviciene R, Kirkwood JS, Kulinich AO, Umemori J, Bhatia A, Hur M, Käkelä R, Ethell IM, and Castrén ML
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- Male, Animals, Mice, Humans, Astrocytes, Lipid Metabolism, Cytokines, Homeostasis, Fragile X Syndrome genetics, Induced Pluripotent Stem Cells
- Abstract
Cholesterol is an essential membrane structural component and steroid hormone precursor, and is involved in numerous signaling processes. Astrocytes regulate brain cholesterol homeostasis and they supply cholesterol to the needs of neurons. ATP-binding cassette transporter A1 (ABCA1) is the main cholesterol efflux transporter in astrocytes. Here we show dysregulated cholesterol homeostasis in astrocytes generated from human induced pluripotent stem cells (iPSCs) derived from males with fragile X syndrome (FXS), which is the most common cause of inherited intellectual disability. ABCA1 levels are reduced in FXS human and mouse astrocytes when compared with controls. Accumulation of cholesterol associates with increased desmosterol and polyunsaturated phospholipids in the lipidome of FXS mouse astrocytes. Abnormal astrocytic responses to cytokine exposure together with altered anti-inflammatory and cytokine profiles of human FXS astrocyte secretome suggest contribution of inflammatory factors to altered cholesterol homeostasis. Our results demonstrate changes of astrocytic lipid metabolism, which can critically regulate membrane properties and affect cholesterol transport in FXS astrocytes, providing target for therapy in FXS., (© 2023. The Author(s).)
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- 2023
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22. Small mitochondrial protein NERCLIN regulates cardiolipin homeostasis and mitochondrial ultrastructure.
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Konovalova S, Torregrosa-Muñumer R, Manjunath P, Liu X, Baral S, Fatima K, Holopainen M, Kvist J, Rajendran J, Yang Y, Varjosalo M, Käkelä R, Somerharju P, and Tyynismaa H
- Subjects
- Animals, Mitochondria genetics, Mitochondria metabolism, Mitochondrial Membranes metabolism, Homeostasis, Mitochondrial Proteins genetics, Mitochondrial Proteins metabolism, Cardiolipins metabolism
- Abstract
Cardiolipin (CL) is an essential phospholipid for mitochondrial structure and function. Here, we present a small mitochondrial protein, NERCLIN, as a negative regulator of CL homeostasis and mitochondrial ultrastructure. Primate-specific NERCLIN is expressed ubiquitously from the GRPEL2 locus on a tightly regulated low level. NERCLIN overexpression severely disrupts mitochondrial cristae structure and induces mitochondrial fragmentation. Proximity labeling and immunoprecipitation analysis suggested interactions of NERCLIN with CL synthesis and prohibitin complexes on the matrix side of the inner mitochondrial membrane. Lipid analysis indicated that NERCLIN regulates mitochondrial CL content. Furthermore, NERCLIN is responsive to heat stress ensuring OPA1 processing and cell survival. Thus, we propose that NERCLIN contributes to the stress-induced adaptation of mitochondrial dynamics. Our findings add NERCLIN to the group of recently identified small mitochondrial proteins with important regulatory functions.
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- 2023
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23. Fatty acid fingerprints in bronchoalveolar lavage fluid and its extracellular vesicles reflect equine asthma severity.
- Author
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Höglund N, Nieminen P, Mustonen AM, Käkelä R, Tollis S, Koho N, Holopainen M, Ruhanen H, and Mykkänen A
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- Animals, Horses, Bronchoalveolar Lavage Fluid chemistry, Fatty Acids, Gas Chromatography-Mass Spectrometry, Bronchoalveolar Lavage, Asthma diagnosis, Asthma veterinary, Extracellular Vesicles, Horse Diseases diagnosis
- Abstract
Equine asthma (EA) is an inflammatory disease of the lower airways driven by mediators released from cells. Extracellular vesicles (EVs) are vehicles for lipid mediators, which possess either pro-inflammatory or dual anti-inflammatory and pro-resolving functions. In this study, we investigated how the respiratory fatty acid (FA) profile reflects airway inflammatory status. The FA composition of bronchoalveolar lavage fluid (BALF), BALF supernatant, and bronchoalveolar EVs of healthy horses (n = 15) and horses with mild/moderate EA (n = 10) or severe EA (SEA, n = 5) was determined with gas chromatography and mass spectrometry. The FA profiles distinguished samples with different diagnoses in all sample types, yet they were insufficient to predict the health status of uncategorized samples. Different individual FAs were responsible for the discrimination of the diagnoses in different sample types. Particularly, in the EVs of SEA horses the proportions of palmitic acid (16:0) decreased and those of eicosapentaenoic acid (20:5n-3) increased, and all sample types of asthmatic horses had elevated dihomo-γ-linolenic acid (20:3n-6) proportions. The results suggest simultaneous pro-inflammatory and resolving actions of FAs and a potential role for EVs as vehicles for lipid mediators in asthma pathogenesis. EV lipid manifestations of EA can offer translational targets to study asthma pathophysiology and treatment options., (© 2023. The Author(s).)
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- 2023
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24. AdipoR2 recruits protein interactors to promote fatty acid elongation and membrane fluidity.
- Author
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Ruiz M, Devkota R, Kaper D, Ruhanen H, Busayavalasa K, Radović U, Henricsson M, Käkelä R, Borén J, and Pilon M
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- Animals, Humans, HEK293 Cells, Phospholipids metabolism, Protein Binding, Caenorhabditis elegans cytology, Caenorhabditis elegans metabolism, Caenorhabditis elegans Proteins genetics, Caenorhabditis elegans Proteins metabolism, Cell Membrane metabolism, Fatty Acids metabolism, Membrane Fluidity physiology, Receptors, Adiponectin metabolism
- Abstract
The human AdipoR2 and its Caenorhabditis elegans homolog PAQR-2 are multipass plasma membrane proteins that protect cells against membrane rigidification. However, how AdipoR2 promotes membrane fluidity mechanistically is not clear. Using 13C-labeled fatty acids, we show that AdipoR2 can promote the elongation and incorporation of membrane-fluidizing polyunsaturated fatty acids into phospholipids. To elucidate the molecular basis of these activities, we performed immunoprecipitations of tagged AdipoR2 and PAQR-2 expressed in HEK293 cells or whole C. elegans, respectively, and identified coimmunoprecipitated proteins using mass spectrometry. We found that several of the evolutionarily conserved AdipoR2/PAQR-2 interactors are important for fatty acid elongation and incorporation into phospholipids. We experimentally verified some of these interactions, namely, with the dehydratase HACD3 that is essential for the third of four steps in long-chain fatty acid elongation and ACSL4 that is important for activation of unsaturated fatty acids and their channeling into phospholipids. We conclude that AdipoR2 and PAQR-2 can recruit protein interactors to promote the production and incorporation of unsaturated fatty acids into phospholipids., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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25. Lipoprotein(a) induces caspase-1 activation and IL-1 signaling in human macrophages.
- Author
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Lorey MB, Youssef A, Äikäs L, Borrelli M, Hermansson M, Assini JM, Kemppainen A, Ruhanen H, Ruuth M, Matikainen S, Kovanen PT, Käkelä R, Boffa MB, Koschinsky ML, and Öörni K
- Abstract
Introduction: Lipoprotein(a) (Lp(a)) is an LDL-like particle with an additional apolipoprotein (apo)(a) covalently attached. Elevated levels of circulating Lp(a) are a risk factor for atherosclerosis. A proinflammatory role for Lp(a) has been proposed, but its molecular details are incompletely defined., Methods and Results: To explore the effect of Lp(a) on human macrophages we performed RNA sequencing on THP-1 macrophages treated with Lp(a) or recombinant apo(a), which showed that especially Lp(a) induces potent inflammatory responses. Thus, we stimulated THP-1 macrophages with serum containing various Lp(a) levels to investigate their correlations with cytokines highlighted by the RNAseq, showing significant correlations with caspase-1 activity and secretion of IL-1β and IL-18. We further isolated both Lp(a) and LDL particles from three donors and then compared their atheroinflammatory potentials together with recombinant apo(a) in primary and THP-1 derived macrophages. Compared with LDL, Lp(a) induced a robust and dose-dependent caspase-1 activation and release of IL-1β and IL-18 in both macrophage types. Recombinant apo(a) strongly induced caspase-1 activation and IL-1β release in THP-1 macrophages but yielded weak responses in primary macrophages. Structural analysis of these particles revealed that the Lp(a) proteome was enriched in proteins associated with complement activation and coagulation, and its lipidome was relatively deficient in polyunsaturated fatty acids and had a high n-6/n-3 ratio promoting inflammation., Discussion: Our data show that Lp(a) particles induce the expression of inflammatory genes, and Lp(a) and to a lesser extent apo(a) induce caspase-1 activation and IL-1 signaling. Major differences in the molecular profiles between Lp(a) and LDL contribute to Lp(a) being more atheroinflammatory., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Lorey, Youssef, Äikäs, Borrelli, Hermansson, Assini, Kemppainen, Ruhanen, Ruuth, Matikainen, Kovanen, Käkelä, Boffa, Koschinsky and Öörni.)
- Published
- 2023
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26. Equine osteoarthritis modifies fatty acid signatures in synovial fluid and its extracellular vesicles.
- Author
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Mustonen AM, Lehmonen N, Paakkonen T, Raekallio M, Käkelä R, Niemelä T, Mykkänen A, Sihvo SP, and Nieminen P
- Subjects
- Humans, Horses, Animals, Synovial Fluid metabolism, Fatty Acids metabolism, Osteoarthritis metabolism, Joint Diseases, Extracellular Vesicles metabolism, Extracellular Vesicles pathology
- Abstract
Background: Individual fatty acids (FAs) and their derivatives (lipid mediators) with pro-inflammatory or dual anti-inflammatory and pro-resolving properties have potential to influence the health of joint tissues. Osteoarthritis (OA) is an age-associated chronic joint disease that can be featured with altered FA composition in the synovial fluid (SF) of human patients. The counts and cargo of extracellular vesicles (EVs), membrane-bound particles released by synovial joint cells and transporting bioactive lipids, can also be modified by OA. The detailed FA signatures of SF and its EVs have remained unexplored in the horse - a well-recognized veterinary model for OA research., Methods: The aim of the present study was to compare the FA profiles in equine SF and its ultracentrifuged EV fraction between control, contralateral, and OA metacarpophalangeal joints (n = 8/group). The FA profiles of total lipids were determined by gas chromatography and the data compared with univariate and multivariate analyses., Results: The data revealed distinct FA profiles in SF and its EV-enriched pellet that were modified by naturally occurring equine OA. Regarding SFs, linoleic acid (generalized linear model, p = 0.0006), myristic acid (p = 0.003), palmitoleic acid (p < 0.0005), and n-3/n-6 polyunsaturated FA ratio (p < 0.0005) were among the important variables that separated OA from control samples. In EV-enriched pellets, saturated FAs palmitic acid (p = 0.020), stearic acid (p = 0.002), and behenic acid (p = 0.003) indicated OA. The observed FA modifications are potentially detrimental and could contribute to inflammatory processes and cartilage degradation in OA., Conclusions: Equine OA joints can be distinguished from normal joints based on their FA signatures in SF and its EV-enriched pellet. Clarifying the roles of SF and EV FA compositions in the pathogenesis of OA and their potential as joint disease biomarkers and therapeutic targets warrants future studies., (© 2023. The Author(s).)
- Published
- 2023
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27. Systematic design of cell membrane coating to improve tumor targeting of nanoparticles.
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Liu L, Pan D, Chen S, Martikainen MV, Kårlund A, Ke J, Pulkkinen H, Ruhanen H, Roponen M, Käkelä R, Xu W, Wang J, and Lehto VP
- Subjects
- Humans, Cell Membrane metabolism, Adsorption, Phospholipids metabolism, Nanoparticles, Neoplasms therapy, Neoplasms metabolism
- Abstract
Cell membrane (CM) coating technology is increasingly being applied in nanomedicine, but the entire coating procedure including adsorption, rupture, and fusion is not completely understood. Previously, we showed that the majority of biomimetic nanoparticles (NPs) were only partially coated, but the mechanism underlying this partial coating remains unclear, which hinders the further improvement of the coating technique. Here, we show that partial coating is an intermediate state due to the adsorption of CM fragments or CM vesicles, the latter of which could eventually be ruptured under external force. Such partial coating is difficult to self-repair to achieve full coating due to the limited membrane fluidity. Building on our understanding of the detailed coating process, we develop a general approach for fixing the partial CM coating: external phospholipid is introduced as a helper to increase CM fluidity, promoting the final fusion of lipid patches. The NPs coated with this approach have a high ratio of full coating (~23%) and exhibit enhanced tumor targeting ability in comparison to the NPs coated traditionally (full coating ratio of ~6%). Our results provide a mechanistic basis for fixing partial CM coating towards enhancing tumor accumulation., (© 2022. The Author(s).)
- Published
- 2022
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28. Preservation of microscopic fur, feather, and bast fibers in the Mesolithic ochre grave of Majoonsuo, Eastern Finland.
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Kirkinen T, López-Costas O, Martínez Cortizas A, Sihvo SP, Ruhanen H, Käkelä R, Nyman JE, Mikkola E, Rantanen J, Hertell E, Ahola M, Roiha J, and Mannermaa K
- Subjects
- Animals, Child, Dogs, Fatty Acids, Finland, Humans, Soil, Burial methods, Feathers
- Abstract
The study of animal and plant fibers related to grave furnishing, garments, and grave goods in thousands-of-year-old burials provides new insights into these funerary practices. Their preservation presupposes favorable conditions, where bacterial and fungal activity is at a minimum, as in anaerobic, wet, salty, arid, or frozen environments. The extreme acidic-soil environments (i.e., podzols) of Finland pose a challenge when it comes to studying funerary deposits, as human remains are rarely found. However, its potential to preserve microparticles allows us to approach the funerary event from a totally different point of view. Here, we present the first multiproxy analyses of a Mesolithic deposit from Finland. A red-ochre burial of a child found in Majoonsuo is studied by analyzing 1) microscopic fibers, 2) fatty acids, and 3) physical-chemical (CIELab color, pH, grain size) properties of 60 soil samples and associated materials. The microscopic fibers evidenced the remains of waterfowl downy feathers, a falcon feather fragment, canid and small rodent hairs as well as bast fibers. These could have been used in furnishing the grave and as ornaments or clothes. Canid hairs could belong to a dog inhumation, or more likely to canid fur used as grave good/clothes. Samples with microparticles have more long-chain and unsaturated fatty acids, although animal species identification was not possible. Soil properties indicate that the burial was made in the local soil, adding homogeneous red ochre and removing the coarser material; no bioturbation was found. The highly acidic sandy soil, together with a slight increase in finer particles when ochre is abundant, probably resulted in micro-scale, anoxic conditions that prevented bacterial attack. This study reveals the first animal hairs and feathers from a Finnish Mesolithic funerary context, and provides clues about how their preservation was possible., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2022
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29. Global effects of pharmacologic inhibition of OSBP in human umbilical vein endothelial cells.
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Taskinen JH, Ruhanen H, Matysik S, Käkelä R, and Olkkonen VM
- Subjects
- Cholesterol metabolism, Endoplasmic Reticulum metabolism, Human Umbilical Vein Endothelial Cells metabolism, Humans, Receptors, Steroid metabolism
- Abstract
Oxysterol-binding protein (OSBP) is a cholesterol/PI4P exchanger at contacts of the endoplasmic reticulum (ER) with trans-Golgi network (TGN) and endosomes. Several central endothelial cell (EC) functions depend on adequate cholesterol distribution in cellular membranes. Here we elucidated the effects of pharmacologic OSBP inhibition on the lipidome and transcriptome of human umbilical vein endothelial cells (HUVECs). OSBP was inhibited for 24 h with 25 nM Schweinfurthin G (SWG) or Orsaponin (OSW-1), followed by analyses of cellular cholesterol, 27-hydroxy-cholesterol, and triacylglycerol concentration, phosphatidylserine synthesis rate, the lipidome, as well as lipid droplet staining and western analysis of OSBP protein. Next-generation RNA sequencing of the SWG-treated and control HUVECs and angiogenesis assays were performed. Protein-normalized lipidomes of the inhibitor-treated cells revealed decreases in glycerophospholipids, the most pronounced effect being on phosphatidylserines and the rate of their synthesis, as well as increases in cholesteryl esters, triacylglycerols and lipid droplet number. Transcriptome analysis of SWG-treated cells suggested ER stress responses apparently caused by disturbed cholesterol exit from the ER, as indicated by suppression of cholesterol biosynthetic genes. OSBP was associated with the TGN in the absence of inhibitors and disappeared therefrom in inhibitor-treated cells in a time-dependent manner, coinciding with OSBP reduction on western blots. Prolonged treatment with SWG or OSW-1 inhibited angiogenesis in vitro. To conclude, inhibition of OSBP in primary endothelial cells induced multiple effects on the lipidome, transcriptome changes suggesting ER stress, and disruption of in vitro angiogenic capacity. Thus, OSBP is a crucial regulator of EC lipid homeostasis and angiogenic capacity., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
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30. Fatty Acid Fingerprints and Hyaluronic Acid in Extracellular Vesicles from Proliferating Human Fibroblast-like Synoviocytes.
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Mustonen AM, Paakkonen T, Matilainen J, Rilla K, Käkelä R, Malinen M, Takabe P, Oikari S, Capra J, Sihvo SP, Ryökäs P, and Nieminen P
- Subjects
- Fatty Acids metabolism, Fatty Acids, Unsaturated metabolism, Fibroblasts metabolism, Humans, Hyaluronan Synthases genetics, Hyaluronan Synthases metabolism, Hyaluronic Acid metabolism, PPAR gamma metabolism, Extracellular Vesicles metabolism, Synoviocytes metabolism
- Abstract
Extracellular vesicles (EVs) function as conveyors of fatty acids (FAs) and other bioactive lipids and can modulate the gene expression and behavior of target cells. EV lipid composition influences the fluidity and stability of EV membranes and reflects the availability of lipid mediator precursors. Fibroblast-like synoviocytes (FLSs) secrete EVs that transport hyaluronic acid (HA). FLSs play a central role in inflammation, pannus formation, and cartilage degradation in joint diseases, and EVs have recently emerged as potential mediators of these effects. The aim of the present study was to follow temporal changes in HA and EV secretion by normal FLSs, and to characterize the FA profiles of FLSs and EVs during proliferation. The methods used included nanoparticle tracking analysis, confocal laser scanning microscopy, sandwich-type enzyme-linked sorbent assay, quantitative PCR, and gas chromatography. The expression of hyaluronan synthases 1-3 in FLSs and HA concentrations in conditioned media decreased during cell proliferation. This was associated with elevated proportions of 20:4n-6 and total n-6 polyunsaturated FAs (PUFAs) in high-density cells, reductions in n-3/n-6 PUFA ratios, and up-regulation of cluster of differentiation 44, tumor necrosis factor α , peroxisome proliferator-activated receptor ( PPAR )- α , and PPAR-γ . Compared to the parent FLSs, 16:0, 18:0, and 18:1n-9 were enriched in the EV fraction. EV counts decreased during cell growth, and 18:2n-6 in EVs correlated with the cell count. To conclude, FLS proliferation was featured by increased 20:4n-6 proportions and reduced n-3/n-6 PUFA ratios, and FAs with a low degree of unsaturation were selectively transferred from FLSs into EVs. These FA modifications have the potential to affect membrane fluidity, biosynthesis of lipid mediators, and inflammatory processes in joints, and could eventually provide tools for translational studies to counteract cartilage degradation in inflammatory joint diseases.
- Published
- 2022
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31. High Lipid Content of Prey Fish and n - 3 PUFA Peroxidation Impair the Thiamine Status of Feeding-Migrating Atlantic Salmon ( Salmo salar ) and Is Reflected in Hepatic Biochemical Indices.
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Keinänen M, Nikonen S, Käkelä R, Ritvanen T, Rokka M, Myllylä T, Pönni J, and Vuorinen PJ
- Subjects
- Animals, Docosahexaenoic Acids chemistry, Fatty Acids metabolism, Fatty Acids, Unsaturated, Thiamine, Fatty Acids, Omega-3 chemistry, Salmo salar metabolism
- Abstract
Signs of impaired thiamine (vitamin B1) status in feeding-migrating Atlantic salmon ( Salmo salar ) were studied in three Baltic Sea areas, which differ in the proportion and nutritional composition of prey fish sprat ( Sprattus sprattus ) and herring (Clupea harengus) . The concentration of n - 3 polyunsaturated fatty acids ( n - 3 PUFAs) increased in salmon with dietary lipids and n - 3 PUFAs, and the hepatic peroxidation product malondialdehyde (MDA) concentration increased exponentially with increasing n - 3 PUFA and docosahexaenoic acid (DHA, 22:6 n - 3 ) concentration, whereas hepatic total thiamine concentration, a sensitive indicator of thiamine status, decreased with the increase in both body lipid and n - 3 PUFA or DHA concentration. The hepatic glucose 6-phosphate dehydrogenase activity was suppressed by high dietary lipids. In salmon muscle and in prey fish, the proportion of thiamine pyrophosphate increased, and that of free thiamine decreased, with increasing body lipid content or PUFAs, or merely DHA. The thiamine status of salmon was impaired mainly due to the peroxidation of n - 3 PUFAs, whereas lipids as a source of metabolic energy had less effect. Organochlorines or general oxidative stress did not affect the thiamine status. The amount of lipids, and, specifically, their long-chain n - 3 PUFAs, are thus responsible for generating thiamine deficiency, and not a prey fish species per se.
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- 2022
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32. Metabolic determination of cell fate through selective inheritance of mitochondria.
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Döhla J, Kuuluvainen E, Gebert N, Amaral A, Englund JI, Gopalakrishnan S, Konovalova S, Nieminen AI, Salminen ES, Torregrosa Muñumer R, Ahlqvist K, Yang Y, Bui H, Otonkoski T, Käkelä R, Hietakangas V, Tyynismaa H, Ori A, and Katajisto P
- Subjects
- Animals, Cell Line, Cell Proliferation, Cellular Senescence, Female, Humans, Mammary Glands, Human cytology, Metabolome, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria genetics, Phenotype, Proteome, Mice, Adult Stem Cells metabolism, Cell Differentiation, Cell Lineage, DNA, Mitochondrial genetics, Energy Metabolism, Genes, Mitochondrial, Mammary Glands, Human metabolism, Mitochondria metabolism
- Abstract
Metabolic characteristics of adult stem cells are distinct from their differentiated progeny, and cellular metabolism is emerging as a potential driver of cell fate conversions
1-4 . How these metabolic features are established remains unclear. Here we identified inherited metabolism imposed by functionally distinct mitochondrial age-classes as a fate determinant in asymmetric division of epithelial stem-like cells. While chronologically old mitochondria support oxidative respiration, the electron transport chain of new organelles is proteomically immature and they respire less. After cell division, selectively segregated mitochondrial age-classes elicit a metabolic bias in progeny cells, with oxidative energy metabolism promoting differentiation in cells that inherit old mitochondria. Cells that inherit newly synthesized mitochondria with low levels of Rieske iron-sulfur polypeptide 1 have a higher pentose phosphate pathway activity, which promotes de novo purine biosynthesis and redox balance, and is required to maintain stemness during early fate determination after division. Our results demonstrate that fate decisions are susceptible to intrinsic metabolic bias imposed by selectively inherited mitochondria., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2022
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33. Metabolic gene regulation by Drosophila GATA transcription factor Grain.
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Kokki K, Lamichane N, Nieminen AI, Ruhanen H, Morikka J, Robciuc M, Rovenko BM, Havula E, Käkelä R, and Hietakangas V
- Subjects
- Animals, Gene Expression Regulation genetics, Larva genetics, Sugars metabolism, Transcriptional Activation genetics, Drosophila genetics, Drosophila Proteins genetics, GATA Transcription Factors genetics
- Abstract
Nutrient-dependent gene regulation critically contributes to homeostatic control of animal physiology in changing nutrient landscape. In Drosophila, dietary sugars activate transcription factors (TFs), such as Mondo-Mlx, Sugarbabe and Cabut, which control metabolic gene expression to mediate physiological adaptation to high sugar diet. TFs that correspondingly control sugar responsive metabolic genes under conditions of low dietary sugar remain, however, poorly understood. Here we identify a role for Drosophila GATA TF Grain in metabolic gene regulation under both low and high sugar conditions. De novo motif prediction uncovered a significant over-representation of GATA-like motifs on the promoters of sugar-activated genes in Drosophila larvae, which are regulated by Grain, the fly ortholog of GATA1/2/3 subfamily. grain expression is activated by sugar in Mondo-Mlx-dependent manner and it contributes to sugar-responsive gene expression in the fat body. On the other hand, grain displays strong constitutive expression in the anterior midgut, where it drives lipogenic gene expression also under low sugar conditions. Consistently with these differential tissue-specific roles, Grain deficient larvae display delayed development on high sugar diet, while showing deregulated central carbon and lipid metabolism primarily on low sugar diet. Collectively, our study provides evidence for the role of a metazoan GATA transcription factor in nutrient-responsive metabolic gene regulation in vivo., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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34. Cold-Active Shewanella glacialimarina TZS-4 T nov. Features a Temperature-Dependent Fatty Acid Profile and Putative Sialic Acid Metabolism.
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Qasim MS, Lampi M, Heinonen MK, Garrido-Zabala B, Bamford DH, Käkelä R, Roine E, and Sarin LP
- Abstract
Species of genus Shewanella are among the most frequently identified psychrotrophic bacteria. Here, we have studied the cellular properties, growth dynamics, and stress conditions of cold-active Shewanella strain #4, which was previously isolated from Baltic Sea ice. The cells are rod-shaped of ~2μm in length and 0.5μm in diameter, and they grow between 0 and 25°C, with an optimum at 15°C. The bacterium grows at a wide range of conditions, including 0.5-5.5% w/v NaCl (optimum 0.5-2% w/v NaCl), pH 5.5-10 (optimum pH 7.0), and up to 1mM hydrogen peroxide. In keeping with its adaptation to cold habitats, some polyunsaturated fatty acids, such as stearidonic acid (18:4n-3), eicosatetraenoic acid (20:4n-3), and eicosapentaenoic acid (20:5n-3), are produced at a higher level at low temperature. The genome is 4,456kb in size and has a GC content of 41.12%. Uniquely, strain #4 possesses genes for sialic acid metabolism and utilizes N -acetyl neuraminic acid as a carbon source. Interestingly, it also encodes for cytochrome c3 genes, which are known to facilitate environmental adaptation, including elevated temperatures and exposure to UV radiation. Phylogenetic analysis based on a consensus sequence of the seven 16S rRNA genes indicated that strain #4 belongs to genus Shewanella , closely associated with Shewanella aestuarii with a ~97% similarity, but with a low DNA-DNA hybridization (DDH) level of ~21%. However, average nucleotide identity (ANI) analysis defines strain #4 as a separate Shewanella species (ANI score=76). Further phylogenetic analysis based on the 92 most conserved genes places Shewanella strain #4 into a distinct phylogenetic clade with other cold-active marine Shewanella species. Considering the phylogenetic, phenotypic, and molecular characterization, we conclude that Shewanella strain #4 is a novel species and name it Shewanella glacialimarina sp. nov. TZS-4
T , where glacialimarina means sea ice. Consequently, S. glacialimarina TZS-4T constitutes a promising model for studying transcriptional and translational regulation of cold-active metabolism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Qasim, Lampi, Heinonen, Garrido-Zabala, Bamford, Käkelä, Roine and Sarin.)- Published
- 2021
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35. Repetitive amiodarone administration causes liver damage via adipose tissue ER stress-dependent lipolysis, leading to hepatotoxic free fatty acid accumulation.
- Author
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Hubel E, Fishman S, Holopainen M, Käkelä R, Shaffer O, Houri I, Zvibel I, and Shibolet O
- Subjects
- Adipocytes metabolism, Adipose Tissue drug effects, Adipose Tissue metabolism, Amiodarone metabolism, Animals, Fatty Acid-Binding Proteins metabolism, Fatty Liver metabolism, Lipid Metabolism drug effects, Lipogenesis physiology, Liver drug effects, Liver metabolism, Liver Diseases metabolism, Mice, Triglycerides metabolism, Amiodarone pharmacology, Endoplasmic Reticulum Stress drug effects, Fatty Acids metabolism, Fatty Acids, Nonesterified metabolism, Lipolysis drug effects
- Abstract
Drug-induced liver injury is an emerging form of acute and chronic liver disease that may manifest as fatty liver. Amiodarone (AMD), a widely used antiarrhythmic drug, can cause hepatic injury and steatosis by a variety of mechanisms, not all completely understood. We hypothesized that repetitive AMD administration may induce hepatic lipotoxicity not only via effects on the liver but also via effects on adipose tissue. Indeed, repetitive AMD administration induced endoplasmic reticulum (ER) stress in both liver and adipose tissue. In adipose tissue, AMD reduced lipogenesis and increased lipolysis. Moreover, AMD treatment induced ER stress and ER stress-dependent lipolysis in 3T3L1 adipocytes in vitro. In the liver, AMD caused increased expression of genes encoding proteins involved in fatty acid (FA) uptake and transfer ( Cd36 , Fabp1 , and Fabp4 ), and resulted in increased hepatic accumulation of free FAs, but not of triacylglycerols. In line with this, there was increased expression of hepatic de novo FA synthesis genes. However, AMD significantly reduced the expression of the desaturase Scd1 and elongase Elovl6 , detected at mRNA and protein levels. Accordingly, the FA profile of hepatic total lipids revealed increased accumulation of palmitate, an SCD1 and ELOVL6 substrate, and reduced levels of palmitoleate and cis -vaccenate, products of the enzymes. In addition, AMD-treated mice displayed increased hepatic apoptosis. The studies show that repetitive AMD induces ER stress and aggravates lipolysis in adipose tissue while inducing a lipotoxic hepatic lipid environment, suggesting that AMD-induced liver damage is due to compound insult to liver and adipose tissue. NEW & NOTEWORTHY AMD chronic administration induces hepatic lipid accumulation by several mechanisms, including induction of hepatic ER stress, impairment of β-oxidation, and inhibition of triacylglycerol secretion. Our study shows that repetitive AMD treatment induces not only hepatic ER stress but also adipose tissue ER stress and lipolysis and hepatic accumulation of free fatty acids and enrichment of palmitate in the total lipids. Understanding the toxicity mechanisms of AMD would help devise ways to limit liver damage.
- Published
- 2021
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36. Lipidomic changes of LDL after consumption of Camelina sativa oil, fatty fish and lean fish in subjects with impaired glucose metabolism-A randomized controlled trial.
- Author
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Erkkilä AT, Manninen S, Fredrikson L, Bhalke M, Holopainen M, Ruuth M, Lankinen M, Käkelä R, Öörni K, and Schwab US
- Subjects
- Aged, Animals, Female, Glucose Intolerance blood, Humans, Lipoproteins, LDL blood, Male, Middle Aged, Protein Aggregates, Spectrometry, Mass, Electrospray Ionization, Camellia chemistry, Dietary Fats, Unsaturated administration & dosage, Eating physiology, Fatty Acids, Omega-3 administration & dosage, Fish Oils administration & dosage, Fishes, Glucose Intolerance metabolism, Lipoproteins, LDL metabolism, Plant Oils administration & dosage, alpha-Linolenic Acid administration & dosage
- Abstract
Background: There is little knowledge on the effects of alpha-linolenic acid (ALA) and n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) on the LDL lipidome and aggregation of LDL particles., Objective: We examined if consumption of Camelina sativa oil (CSO) as a source of ALA, fatty fish (FF) as a source of n-3 LCPUFA and lean fish (LF) as a source of fish protein affect the lipidome of LDL as compared to a control diet., Methods: Participants with impaired glucose tolerance (39 women and 40 men) were randomized to 4 study groups (CSO providing 10 g/d ALA, FF and LF [both 4 fish meals/wk] and control limiting their fish and ALA intake) in a 12-week, parallel trial. Diets were instructed and dietary fats were provided to the participants. The lipidome of LDL particles isolated from samples collected at baseline and after intervention was analyzed with electrospray ionization-tandem mass spectrometry., Results: In the CSO group, the relative concentrations of saturated and monounsaturated cholesteryl ester species in LDL decreased and the species with ALA increased. In the FF group, LDL phosphatidylcholine (PC) species containing n-3 LCPUFA increased. There was a significant positive correlation between the change in total sphingomyelin and change in LDL aggregation, while total PC and triunsaturated PC species were inversely associated with LDL aggregation when all the study participants were included in the analysis., Conclusion: Dietary intake of CSO and FF modifies the LDL lipidome to contain more polyunsaturated and less saturated lipid species. The LDL surface lipids are associated with LDL aggregation., Competing Interests: Declaration of Competing Interest K.Ö. and M.R. have applied for a patent in LDL aggregation measurement. The other authors report no conflict of interest., (Copyright © 2021. Published by Elsevier Inc.)
- Published
- 2021
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37. Sex-specific lipid profiles in the muscle of Atlantic salmon juveniles.
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House AH, Debes PV, Kurko J, Erkinaro J, Käkelä R, and Primmer CR
- Subjects
- Animals, Female, Lipids analysis, Lipids genetics, Male, Muscles metabolism, Salmo salar genetics, Sex Characteristics, Lipid Metabolism, Salmo salar growth & development, Salmo salar metabolism
- Abstract
Energy allocation in juvenile fish can have important implications for future life-history progression. Inherited and environmental factors determine when and where individuals allocate energy, and timely and sufficient energy reserves are crucial for reaching key life stages involved in the timing of maturation and sea migration. In Atlantic salmon, lipid reserves are predominantly found in the viscera and myosepta in the muscle and have been shown to play a key role in determining the timing of maturity. This life-history trait is tightly linked to fitness in many species and can be different between males and females, however, the details of relative energy allocation in juveniles of different sexes is not well understood. Therefore, the aim of this study was to investigate the effects of sex, genetics and environment during juvenile development of salmon on the amount and composition of their lipid reserves. To do so, juvenile salmon were fed one of two different lipid food contents during their first summer and autumn under common-garden conditions. Muscle lipid composition and concentrations were determined by thin layer chromatography. The muscle lipid class concentrations covaried negatively with body length and males showed higher concentrations than females for phosphatidylcholine, cholesterol, sphingomyelin, and triacylglycerol. This sex-specific difference in major lipid classes presents a new scope for understanding the regulation of lipids during juvenile development and gives direction for understanding how lipids may interact and influence major life-history traits in Atlantic salmon., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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38. Streptococcus pneumoniae pneumolysin and neuraminidase A convert high-density lipoproteins into pro-atherogenic particles.
- Author
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Syed S, Nissilä E, Ruhanen H, Fudo S, Gaytán MO, Sihvo SP, Lorey MB, Metso J, Öörni K, King SJ, Oommen OP, Jauhiainen M, Meri S, Käkelä R, and Haapasalo K
- Abstract
High-density lipoproteins (HDLs) are a group of different subpopulations of sialylated particles that have an essential role in the reverse cholesterol transport (RCT) pathway. Importantly, changes in the protein and lipid composition of HDLs may lead to the formation of particles with reduced atheroprotective properties. Here, we show that Streptococcus pneumoniae pneumolysin (PLY) and neuraminidase A (NanA) impair HDL function by causing chemical and structural modifications of HDLs. The proteomic, lipidomic, cellular, and biochemical analysis revealed that PLY and NanA induce significant changes in sialic acid, protein, and lipid compositions of HDL. The modified HDL particles have reduced cholesterol acceptor potential from activated macrophages, elevated levels of malondialdehyde adducts, and show significantly increased complement activating capacity. These results suggest that accumulation of these modified HDL particles in the arterial intima may present a trigger for complement activation, inflammatory response, and thereby promote atherogenic disease progression., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)
- Published
- 2021
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39. Synovial Fluid Fatty Acid Profiles Are Differently Altered by Inflammatory Joint Pathologies in the Shoulder and Knee Joints.
- Author
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Mustonen AM, Käkelä R, Joukainen A, Lehenkari P, Jaroma A, Kääriäinen T, Kröger H, Paakkonen T, Sihvo SP, and Nieminen P
- Abstract
Anomalies of fatty acid (FA) metabolism characterize osteoarthritis (OA) and rheumatoid arthritis (RA) in the knee joint. No previous study has investigated the synovial fluid (SF) FA manifestations in these aging-related inflammatory diseases in the shoulder. The present experiment compared the FA alterations between the shoulder and knee joints in patients with end-stage OA or end-stage RA. SF samples were collected during glenohumeral or knee joint surgery from trauma controls and from OA and RA patients (n = 42). The FA composition of SF total lipids was analyzed by gas chromatography with flame ionization and mass spectrometric detection and compared across cohorts. The FA signatures of trauma controls were mostly uniform in both anatomical locations. RA shoulders were characterized by elevated percentages of 20:4n-6 and 22:6n-3 and with reduced proportions of 18:1n-9. The FA profiles of OA and RA knees were relatively uniform and displayed lower proportions of 18:2n-6, 22:6n-3 and total n-6 polyunsaturated FAs (PUFAs). The results indicate location- and disease-dependent differences in the SF FA composition. These alterations in FA profiles and their potential implications for the production of PUFA-derived lipid mediators may affect joint lubrication, synovial inflammation and pannus formation as well as cartilage and bone degradation and contribute to the pathogeneses of inflammatory joint diseases.
- Published
- 2021
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40. Coordinated control of adiposity and growth by anti-anabolic kinase ERK7.
- Author
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Hasygar K, Deniz O, Liu Y, Gullmets J, Hynynen R, Ruhanen H, Kokki K, Käkelä R, and Hietakangas V
- Subjects
- Animals, Drosophila metabolism, Phosphorylation, Signal Transduction, Adiposity, Extracellular Signal-Regulated MAP Kinases metabolism
- Abstract
Energy storage and growth are coordinated in response to nutrient status of animals. How nutrient-regulated signaling pathways control these processes in vivo remains insufficiently understood. Here, we establish an atypical MAP kinase, ERK7, as an inhibitor of adiposity and growth in Drosophila. ERK7 mutant larvae display elevated triacylglycerol (TAG) stores and accelerated growth rate, while overexpressed ERK7 is sufficient to inhibit lipid storage and growth. ERK7 expression is elevated upon fasting and ERK7 mutant larvae display impaired survival during nutrient deprivation. ERK7 acts in the fat body, the insect counterpart of liver and adipose tissue, where it controls the subcellular localization of chromatin-binding protein PWP1, a growth-promoting downstream effector of mTOR. PWP1 maintains the expression of sugarbabe, encoding a lipogenic Gli-similar family transcription factor. Both PWP1 and Sugarbabe are necessary for the increased growth and adiposity phenotypes of ERK7 loss-of-function animals. In conclusion, ERK7 is an anti-anabolic kinase that inhibits lipid storage and growth while promoting survival on fasting conditions., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2021
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41. The Diapause Lipidomes of Three Closely Related Beetle Species Reveal Mechanisms for Tolerating Energetic and Cold Stress in High-Latitude Seasonal Environments.
- Author
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Lehmann P, Westberg M, Tang P, Lindström L, and Käkelä R
- Abstract
During winter insects face energetic stress driven by lack of food, and thermal stress due to sub-optimal and even lethal temperatures. To survive, most insects living in seasonal environments such as high latitudes, enter diapause, a deep resting stage characterized by a cessation of development, metabolic suppression and increased stress tolerance. The current study explores physiological adaptations related to diapause in three beetle species at high latitudes in Europe. From an ecological perspective, the comparison is interesting since one species ( Leptinotarsa decemlineata ) is an invasive pest that has recently expanded its range into northern Europe, where a retardation in range expansion is seen. By comparing its physiological toolkit to that of two closely related native beetles ( Agelastica alni and Chrysolina polita ) with similar overwintering ecology and collected from similar latitude, we can study if harsh winters might be constraining further expansion. Our results suggest all species suppress metabolism during diapause and build large lipid stores before diapause, which then are used sparingly. In all species diapause is associated with temporal shifts in storage and membrane lipid profiles, mostly in accordance with the homeoviscous adaptation hypothesis, stating that low temperatures necessitate acclimation responses that increase fluidity of storage lipids, allowing their enzymatic hydrolysis, and ensure integral protein functions. Overall, the two native species had similar lipidomic profiles when compared to the invasive species, but all species showed specific shifts in their lipid profiles after entering diapause. Taken together, all three species show adaptations that improve energy saving and storage and membrane lipid fluidity during overwintering diapause. While the three species differed in the specific strategies used to increase lipid viscosity, the two native beetle species showed a more canalized lipidomic response, than the recent invader. Since close relatives with similar winter ecology can have different winter ecophysiology, extrapolations among species should be done with care. Still, range expansion of the recent invader into high latitude habitats might indeed be retarded by lack of physiological tools to manage especially thermal stress during winter, but conversely species adapted to long cold winters may face these stressors as a consequence of ongoing climate warming., (Copyright © 2020 Lehmann, Westberg, Tang, Lindström and Käkelä.)
- Published
- 2020
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42. Plant Stanol Esters Reduce LDL (Low-Density Lipoprotein) Aggregation by Altering LDL Surface Lipids: The BLOOD FLOW Randomized Intervention Study.
- Author
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Ruuth M, Äikäs L, Tigistu-Sahle F, Käkelä R, Lindholm H, Simonen P, Kovanen PT, Gylling H, and Öörni K
- Subjects
- Adult, Aged, Biomarkers blood, Cholesterol, LDL blood, Double-Blind Method, Female, Finland, Humans, Hypercholesterolemia blood, Hypercholesterolemia diagnosis, Lipidomics, Male, Middle Aged, Proteoglycans blood, Sphingomyelins blood, Time Factors, Treatment Outcome, Triglycerides blood, Young Adult, Diet, Esters administration & dosage, Hypercholesterolemia diet therapy, Lipoproteins, LDL blood, Phytosterols administration & dosage, Protein Aggregates
- Abstract
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<25 kg/m
2 . Decreased LDL aggregation susceptibility was associated with decreased proportion of LDL-sphingomyelins and increased proportion of LDL-triacylglycerols. LDL binding to proteoglycans was decreased in the plant stanol ester group, the decrease depending on decreased serum LDL-cholesterol concentration., 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.- Published
- 2020
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43. ANGPTL3 deficiency alters the lipid profile and metabolism of cultured hepatocytes and human lipoproteins.
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Ruhanen H, Haridas PAN, Minicocci I, Taskinen JH, Palmas F, di Costanzo A, D'Erasmo L, Metso J, Partanen J, Dalli J, Zhou Y, Arca M, Jauhiainen M, Käkelä R, and Olkkonen VM
- Subjects
- Adult, Aged, Angiopoietin-Like Protein 3, Angiopoietin-like Proteins genetics, Cell Line, Female, Humans, Lipoproteins blood, Male, Middle Aged, Triglycerides metabolism, Angiopoietin-like Proteins metabolism, Hepatocytes metabolism, Lipid Metabolism, Lipoproteins metabolism, Loss of Function Mutation
- Abstract
Loss-of-function (LOF) mutations in ANGPTL3, an inhibitor of lipoprotein lipase (LPL), cause a drastic reduction of serum lipoproteins and protect against the development of atherosclerotic cardiovascular disease. Therefore, ANGPTL3 is a promising therapy target. We characterized the impacts of ANGPTL3 depletion on the immortalized human hepatocyte (IHH) transcriptome, lipidome and human plasma lipoprotein lipidome. The transcriptome of ANGPTL3 knock-down (KD) cells showed altered expression of several pathways related to lipid metabolism. Accordingly, ANGPTL3 depleted IHH displayed changes in cellular overall fatty acid (FA) composition and in the lipid species composition of several lipid classes, characterized by abundant n-6 and n-3 polyunsaturated FAs (PUFAs). This PUFA increase coincided with an elevation of lipid mediators, among which there were species relevant for resolution of inflammation, protection from lipotoxic and hypoxia-induced ER stress, hepatic steatosis and insulin resistance or for the recovery from cardiovascular events. Cholesterol esters were markedly reduced in ANGPTL3 KD IHH, coinciding with suppression of the SOAT1 mRNA and protein. ANGPTL3 LOF caused alterations in plasma lipoprotein FA and lipid species composition. All lipoprotein fractions of the ANGPTL3 LOF subjects displayed a marked drop of 18:2n-6, while several highly unsaturated triacylglycerol (TAG) species were enriched. The present work reveals distinct impacts of ANGPTL3 depletion on the hepatocellular lipidome, transcriptome and lipid mediators, as well as on the lipidome of lipoproteins isolated from plasma of ANGPTL3-deficient human subjects. It is important to consider these lipidomics and transcriptomics findings when targeting ANGPTL3 for therapy and translating it to the human context., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)
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- 2020
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44. Orotic acid-treated hepatocellular carcinoma cells resist steatosis by modification of fatty acid metabolism.
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Matilainen J, Mustonen AM, Rilla K, Käkelä R, Sihvo SP, and Nieminen P
- Subjects
- Carcinoma, Hepatocellular genetics, Discriminant Analysis, Gene Expression Regulation, Neoplastic drug effects, Hep G2 Cells, Humans, Inflammation pathology, Lipogenesis drug effects, Lipopolysaccharides, Liver Neoplasms genetics, Orotic Acid pharmacology, RNA, Messenger genetics, RNA, Messenger metabolism, Stearoyl-CoA Desaturase genetics, Stearoyl-CoA Desaturase metabolism, Triglycerides metabolism, Carcinoma, Hepatocellular drug therapy, Carcinoma, Hepatocellular metabolism, Fatty Acids metabolism, Liver Neoplasms drug therapy, Liver Neoplasms metabolism, Non-alcoholic Fatty Liver Disease metabolism, Orotic Acid therapeutic use
- Abstract
Background: Orotic acid (OA) has been intensively utilized to induce fatty liver in rats. Although the capacity of OA to cause steatosis is species-specific, previous in vitro studies indicate that humans could also be susceptible to OA-induced fatty liver. The aim of the present study was to re-elucidate the potential of OA exposure to modulate the cellular mechanisms involved in both non-alcoholic fatty liver disease pathogenesis and cellular protection from lipid accumulation. In addition, alterations in detailed fatty acid (FA) profiles of cells and culture media were analyzed to assess the significance of lipid metabolism in these phenomena., Methods: In our experiments, human hepatocellular carcinoma HepG2 cells were exposed to OA. Bacterial endotoxin, lipopolysaccharide (LPS), was used to mimic hepatic inflammation. The lipogenic and inflammatory effects of OA and/or LPS on cells were assessed by labeling cellular lipids with Nile red stain and by performing image quantifications. The expression levels of key enzymes involved in de novo lipogenesis (DNL) and of inflammatory markers related to the disease development were studied by qRT-PCR. FA profiles of cells and culture media were determined from total lipids with gas chromatography-mass spectrometry., Results: Our data indicate that although OA possibly promotes the first stage of DNL, it does not cause a definite lipogenic transformation in HepG2 cells. Reduced proportions of 16:0, increased stearoyl-Coenzyme A desaturase 1 mRNA expression and relatively high proportions of 16:1n-7 suggest that active delta9-desaturation may limit lipogenesis and the accumulation of toxic 16:0. Inflammatory signaling could be reduced by the increased production of long-chain n-3 polyunsaturated FA (PUFA) and the active incorporation of certain FA, including 18:1n-9, into cells. In addition, increased proportions of 20:4n-6 and 22:6n-3, total PUFA and dimethyl acetal 18:0 suggest that OA exposure may cause increased secretion of lipoproteins and extracellular vesicles., Conclusions: The present data suggest that, apart from the transcription-level events reported by previous studies, modifications of FA metabolism may also be involved in the prevention of OA-mediated steatosis. Increased delta9-desaturation and secretion of lipoproteins and extracellular vesicles could offer potential mechanisms for further studies to unravel how OA-treated cells alleviate lipidosis.
- Published
- 2020
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45. Treatment Profile and 1-Year Mortality Among Nontraumatic Intensive Care Unit Patients With Alcohol-Related Health Problems.
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Hietanen S, Ala-Kokko T, Ohtonen P, Käkelä R, Niemelä S, and Liisanantti JH
- Subjects
- APACHE, Aged, Alcohol-Related Disorders therapy, Critical Care, Female, Humans, Male, Middle Aged, Retrospective Studies, Survival Rate, Alcohol-Related Disorders mortality, Hospitalization statistics & numerical data, Intensive Care Units statistics & numerical data
- Abstract
Background: Long-term excessive use of alcohol leads to severe complications, which often require treatment in an intensive care unit (ICU). The aim of this study was to report on the associations between alcohol-related health problems and treatment profile, as well as 1-year mortality among patients with nontrauma-related ICU admissions., Methods: Information on the history of alcohol-related health problems or excessive alcohol use and ICU treatment was collected retrospectively from electronic medical records and ICU patient data management systems at Oulu University Hospital, Finland. Information on 1-year mortality was obtained from the Finnish Population Register Center., Results: According to the medical records, in a total of 899 admissions, 32.9% (n = 296) of patients had a history of alcohol-related problems. In the alcohol group, intoxications were more frequent and respiratory and cardiovascular causes were less frequent, compared to those without alcohol-related problems. Patients without alcohol-related problems had a higher rate of previous comorbidities compared with the alcohol group. There were no differences concerning age, severity of illness scores, length of stay, or intensive care outcome. Mortality during the 1-year follow-up was 32.8% in total: 35.1% among those without alcohol-related history and 28.0% in the alcohol group ( P = .041). The difference in mortality appeared during the first month following admission and remained throughout the follow-up period. The highest 1-year mortality (59.3%) was observed among patients with alcohol-related liver disease., Conclusion: Every third patient admitted to ICU used alcohol excessively or had alcohol-related diseases, and those patients with alcohol-related liver disease had the poorest 1-year survival rate. We found higher long-term mortality in nonalcohol-related admissions, which can be explained by the case mix, including a lower rate of chronic diseases, such as malignancies and coronary artery disease, and a higher rate of low-risk admission diagnoses in the alcohol group.
- Published
- 2020
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46. A transposable element insertion is associated with an alternative life history strategy.
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Woronik A, Tunström K, Perry MW, Neethiraj R, Stefanescu C, Celorio-Mancera MP, Brattström O, Hill J, Lehmann P, Käkelä R, and Wheat CW
- Subjects
- Animals, CRISPR-Cas Systems genetics, Color, Female, Gene Editing methods, Gene Expression Profiling, Gene Expression Regulation, Developmental, Homeodomain Proteins metabolism, Male, Pigmentation genetics, Pigments, Biological biosynthesis, Reproduction genetics, Sex Factors, Whole Genome Sequencing, Wings, Animal metabolism, Wings, Animal ultrastructure, Butterflies physiology, DNA Transposable Elements genetics, Genetic Loci, Homeodomain Proteins genetics, Life History Traits
- Abstract
Tradeoffs affect resource allocation during development and result in fitness consequences that drive the evolution of life history strategies. Yet despite their importance, we know little about the mechanisms underlying life history tradeoffs. Many species of Colias butterflies exhibit an alternative life history strategy (ALHS) where females divert resources from wing pigment synthesis to reproductive and somatic development. Due to this reallocation, a wing color polymorphism is associated with the ALHS: either yellow/orange or white. Here we map the locus associated with this ALHS in Colias crocea to a transposable element insertion located downstream of the Colias homolog of BarH-1, a homeobox transcription factor. Using CRISPR/Cas9 gene editing, antibody staining, and electron microscopy we find white-specific expression of BarH-1 suppresses the formation of pigment granules in wing scales and gives rise to white wing color. Lipid and transcriptome analyses reveal physiological differences associated with the ALHS. Together, these findings characterize a mechanism for a female-limited ALHS.
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- 2019
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47. LDL aggregation susceptibility is higher in healthy South Asian compared with white Caucasian men.
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Ruuth M, Janssen LGM, Äikäs L, Tigistu-Sahle F, Nahon KJ, Ritvos O, Ruhanen H, Käkelä R, Boon MR, Öörni K, and Rensen PCN
- Subjects
- Adolescent, Adult, Animals, Arteriosclerosis metabolism, Asian People, CHO Cells, Cricetulus, Cross-Sectional Studies, Humans, Male, Mass Spectrometry, Sphingomyelin Phosphodiesterase therapeutic use, Triglycerides metabolism, White People, Young Adult, Arteriosclerosis blood, Lipoproteins, LDL blood, Lipoproteins, LDL metabolism, Triglycerides blood
- Abstract
Background: South Asians are more prone to develop atherosclerotic cardiovascular disease (ASCVD) compared with white Caucasians, which is not fully explained by classical risk factors. We recently reported that the presence of aggregation-prone low-density lipoprotein (LDL) in the circulation is associated with increased ASCVD mortality., Objective: We hypothesized that LDL of South Asians is more prone to aggregate, which may be explained by differences in their LDL lipid composition., Methods: In this cross-sectional hypothesis-generating study, LDL was isolated from plasma of healthy South Asians (n = 12) and age- and BMI-matched white Caucasians (n = 12), and its aggregation susceptibility and lipid composition were analyzed., Results: LDL from South Asians was markedly more prone to aggregate compared with white Caucasians. Among all measured lipids, sphingomyelin 24:0 and triacylglycerol 56:8 showed the highest positive correlation with LDL aggregation. In addition, LDL from South Asians was enriched in arachidonic acid containing phosphatidylcholine 38:4 and had less phosphatidylcholines and cholesteryl esters containing monounsaturated fatty acids. Interestingly, body fat percentage, which was higher in South Asians (+26%), positively correlated with LDL aggregation and highly positively correlated with triacylglycerol 56:8, sphingomyelin 24:0, and total sphingomyelin., Conclusions: LDL aggregation susceptibility is higher in healthy young South Asians compared with white Caucasians. This may be partly explained by the higher body fat percentage of South Asians, leading to sphingomyelin enrichment of LDL. We anticipate that the presence of sphingomyelin-rich, aggregation-prone LDL particles in young South Asians may increase LDL accumulation in the arterial wall and thereby contribute to their increased risk of developing ASCVD later in life., (Copyright © 2019 National Lipid Association. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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48. Polyunsaturated fatty acids modify the extracellular vesicle membranes and increase the production of proresolving lipid mediators of human mesenchymal stromal cells.
- Author
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Holopainen M, Colas RA, Valkonen S, Tigistu-Sahle F, Hyvärinen K, Mazzacuva F, Lehenkari P, Käkelä R, Dalli J, Kerkelä E, and Laitinen S
- Subjects
- Cells, Cultured, Dinoprostone metabolism, Fatty Acids metabolism, Humans, Phospholipids metabolism, Extracellular Vesicles metabolism, Fatty Acids, Unsaturated metabolism, Inflammation Mediators metabolism, Mesenchymal Stem Cells metabolism
- Abstract
Human mesenchymal stromal/stem cells (hMSCs) are used in experimental cell therapy to treat various immunological disorders, and the extracellular vesicles (hMSC-EVs) they produce have emerged as an option for cell-free therapeutics. The immunomodulatory function of hMSCs resembles the resolution of inflammation, in which proresolving lipid mediators (LMs) play key roles. Multiple mechanisms underlying the hMSC immunosuppressive effect has been elucidated; however, the impact of LMs and EVs in the resolution is poorly understood. In this study, we supplemented hMSCs with polyunsaturated fatty acids (PUFAs); arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid, which serve as precursors for multiple LMs. We then determined the consequent compositional modifications in the fatty acid, phospholipid, and LM profiles. Mass spectrometric analyses revealed that the supplemented PUFAs were incorporated into the main membrane phospholipid classes with different dynamics, with phosphatidylcholine serving as the first acceptor. Most importantly, the PUFA modifications were transferred into hMSC-EVs, which are known to mediate hMSC immunomodulation. Furthermore, the membrane-incorporated PUFAs influenced the LM profile by increasing the production of downstream prostaglandin E
2 and proresolving LMs, including Resolvin E2 and Resolvin D6. The production of LMs was further enhanced by a highly proinflammatory stimulus, which resulted in an increase in a number of mediators, most notably prostaglandins, while other stimulatory conditions had less a pronounced impact after a 48-h incubation. The current findings suggest that PUFA manipulations of hMSCs exert significant immunomodulatory effects via EVs and proresolving LMs, the composition of which can be modified to potentiate the therapeutic impact of hMSCs., (Copyright © 2019 Elsevier B.V. All rights reserved.)- Published
- 2019
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49. Lipid mediators in platelet concentrate and extracellular vesicles: Molecular mechanisms from membrane glycerophospholipids to bioactive molecules.
- Author
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Valkonen S, Holopainen M, Colas RA, Impola U, Dalli J, Käkelä R, Siljander PR, and Laitinen S
- Subjects
- Cell Membrane chemistry, Extracellular Vesicles physiology, Humans, Inflammation Mediators analysis, Mass Spectrometry methods, Platelet Transfusion adverse effects, Platelet Transfusion standards, Blood Platelets cytology, Blood Preservation, Extracellular Vesicles chemistry, Glycerophospholipids analysis
- Abstract
Platelets are collected for transfusion to patients with different haematological disorders, and for logistical reasons, platelets are stored as concentrates. Despite carefully controlled conditions, platelets become activated during storage, and platelet concentrates (PlaCs) may cause adverse inflammatory reactions in recipients. The time-dependent changes in the lipidome of clinical PlaCs, platelets isolated from PlaCs, and extracellular vesicles (EVs) thereof were examined by mass spectrometry. The relative amount of arachidonic acid containing glycerophospholipids, especially those in the phosphatidylethanolamine and phosphatidylserine classes during storage, but the relative amount of other polyunsaturated fatty acid containing glycerophospholipids remained stable in all sample types. These changes were not directly translated to lipid mediator (LM) profile since the levels of arachidonic acid-derived proinflammatory LMs were not specifically elevated. Instead, several monohydroxy pathway markers and functionally relevant LMs, both proinflammatory and proresolving, were detected in the PlaCs and the EVs, and some representatives of both kind clearly accumulated during storage. By Western blot, the key enzymes of these pathways were shown to be present in platelets, and in many cases, EVs. Since the EVs were enriched in the fatty acid precursors of LMs in their (phospholipid) membranes, harboured LM-producing enzymes, contained the related monohydroxy pathway markers, and secreted the final LM products, PlaC-derived EVs could participate in the regulation of inflammation and healing, and thereby aid the platelets in exerting their essential physiological functions., (Copyright © 2019. Published by Elsevier B.V.)
- Published
- 2019
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50. Lysosomal proteome analysis reveals that CLN3-defective cells have multiple enzyme deficiencies associated with changes in intracellular trafficking.
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Schmidtke C, Tiede S, Thelen M, Käkelä R, Jabs S, Makrypidi G, Sylvester M, Schweizer M, Braren I, Brocke-Ahmadinejad N, Cotman SL, Schulz A, Gieselmann V, and Braulke T
- Subjects
- Animals, Hydrolases metabolism, Membrane Glycoproteins genetics, Membrane Glycoproteins metabolism, Mice, Molecular Chaperones genetics, Molecular Chaperones metabolism, Receptors, Transferrin metabolism, Cerebellum metabolism, Lipids analysis, Lysosomes metabolism, Membrane Glycoproteins deficiency, Protein Transport, Proteins metabolism, Proteome analysis
- Abstract
Numerous lysosomal enzymes and membrane proteins are essential for the degradation of proteins, lipids, oligosaccharides, and nucleic acids. The CLN3 gene encodes a lysosomal membrane protein of unknown function, and CLN3 mutations cause the fatal neurodegenerative lysosomal storage disorder CLN3 (Batten disease) by mechanisms that are poorly understood. To define components critical for lysosomal homeostasis that are affected by this disease, here we quantified the lysosomal proteome in cerebellar cell lines derived from a CLN3 knock-in mouse model of human Batten disease and control cells. We purified lysosomes from SILAC-labeled, and magnetite-loaded cerebellar cells by magnetic separation and analyzed them by MS. This analysis identified 70 proteins assigned to the lysosomal compartment and 3 lysosomal cargo receptors, of which most exhibited a significant differential abundance between control and CLN3-defective cells. Among these, 28 soluble lysosomal proteins catalyzing the degradation of various macromolecules had reduced levels in CLN3-defective cells. We confirmed these results by immunoblotting and selected protease and glycosidase activities. The reduction of 11 lipid-degrading lysosomal enzymes correlated with reduced capacity for lipid droplet degradation and several alterations in the distribution and composition of membrane lipids. In particular, levels of lactosylceramides and glycosphingolipids were decreased in CLN3-defective cells, which were also impaired in the recycling pathway of the exocytic transferrin receptor. Our findings suggest that CLN3 has a crucial role in regulating lysosome composition and their function, particularly in degrading of sphingolipids, and, as a consequence, in membrane transport along the recycling endosome pathway., (© 2019 Schmidtke et al.)
- Published
- 2019
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