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Hyötyläinen, TuuliaORCID iD iconorcid.org/0000-0002-4382-4355
Publications (10 of 185) Show all publications
Nilén, G., Larsson, M., Hyötyläinen, T. & Keiter, S. (2024). A complex mixture of polycyclic aromatic compounds causes embryotoxic, behavioral, and molecular effects in zebrafish larvae (Danio rerio), and in vitro bioassays. Science of the Total Environment, 906, Article ID 167307.
Open this publication in new window or tab >>A complex mixture of polycyclic aromatic compounds causes embryotoxic, behavioral, and molecular effects in zebrafish larvae (Danio rerio), and in vitro bioassays
2024 (English)In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 906, article id 167307Article in journal (Refereed) Published
Abstract [en]

Polycyclic aromatic compounds (PACs) are prevalent in the environment, typically found in complex mixtures and high concentrations. Our understanding of the effects of PACs, excluding the 16 priority polycyclic aromatic hydrocarbons (16 PAHs), remains limited. Zebrafish embryos and in vitro bioassays were utilized to investigate the embryotoxic, behavioral, and molecular effects of a soil sample from a former gasworks site in Sweden. Additionally, targeted chemical analysis was conducted to analyze 87 PACs in the soil, fish, water, and plate material. CALUX® assays were used to assess the activation of aryl hydrocarbon and estrogen receptors, as well as the inhibition of the androgen receptor. Larval behavior was measured by analyzing activity during light and darkness and in response to mechanical stimulation. Furthermore, qPCR analyses were performed on a subset of 36 genes associated with specific adverse outcomes, and the total lipid content in the larvae was measured. Exposure to the sample resulted in embryotoxic effects (LC50 = 0.480 mg dry matter soil/mL water). The mixture also induced hyperactivity in darkness and hypoactivity in light and in response to the mechanical stimulus. qPCR analysis revealed differential regulation of 15 genes, including downregulation of opn1sw1 (eye pigmentation) and upregulation of fpgs (heart failure). The sample caused significant responses in three bioassays (ERα-, DR-, and PAH-CALUX), and the exposed larvae exhibited elevated lipid levels. Chemical analysis identified benzo[a]pyrene as the predominant compound in the soil and approximately half of the total PAC concentration was attributed to the 16 PAHs. This study highlights the value of combining in vitro and in vivo methods with chemical analysis to assess toxic mechanisms at specific targets and to elucidate the possible interactions between various pathways in an organism. It also enhances our understanding of the risks associated with environmental mixtures of PACs and their distribution during toxicity testing.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Chemical analysis, Environment, Gasworks, Lipidomics, Quantitative gene expression, Soil
National Category
Environmental Sciences
Identifiers
urn:nbn:se:oru:diva-108825 (URN)10.1016/j.scitotenv.2023.167307 (DOI)001102592900001 ()37804991 (PubMedID)2-s2.0-85173583428 (Scopus ID)
Funder
Knowledge Foundation, 201660019
Available from: 2023-10-10 Created: 2023-10-10 Last updated: 2023-12-15Bibliographically approved
Karlsson, J., Lopez-Sanchez, P., Marques, T. M., Hyötyläinen, T., Castro Alves, V., Krona, A. & Ström, A. (2024). Effect of heating of pea fibres on their swelling, rheological properties and in vitro colon fermentation. Food Hydrocolloids, 147, Article ID 109306.
Open this publication in new window or tab >>Effect of heating of pea fibres on their swelling, rheological properties and in vitro colon fermentation
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2024 (English)In: Food Hydrocolloids, ISSN 0268-005X, E-ISSN 1873-7137, Vol. 147, article id 109306Article in journal (Refereed) Published
Abstract [en]

Dietary fibre intake is essential for all human beings and has been correlated to beneficial health effects. Pea hull fibres (PF) are generally seen as a side stream during extraction of protein and starch from yellow pea but could be used in various food products to boost fibre content. In this study, the thermal treatment of pea hull fibres was investigated in terms of physicochemical properties and in vitro colonic fermentation. The PF that was subjected to heating showed an increase of fibres solubilised in the liquid and particle size. Results also showed that viscosity and storage modulus increased with thermal treatment, possibly due to the swelling of the PF. The pea fibre was readily fermentable based on total gas production and pH. However, the susceptibility to fermentation of PF did not increase with thermal treatment. Total gas production and short chain fatty acid produced were similar independent of thermal treatment. Conclusively, heating of the PF resulted in increased ability to structure water suspension, owing to increased fibre particle size, but is not sufficient to increase short chain fatty acid production during colonic fermentation. To explain this, we propose that the changes in cell wall structure were not major enough to induce higher fermentability.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Pea hull fibre, In vitro colonic fermentation, Rheology
National Category
Food Science
Identifiers
urn:nbn:se:oru:diva-109022 (URN)10.1016/j.foodhyd.2023.109306 (DOI)001086386500001 ()2-s2.0-85172414777 (Scopus ID)
Funder
Swedish Research Council Formas, 2020-02843
Available from: 2023-10-17 Created: 2023-10-17 Last updated: 2023-11-06Bibliographically approved
Hyötyläinen, T., Ghaffarzadegan, T., Karthikeyan, B. S., Triplett, E., Oresic, M. & Ludvigsson, J. (2024). Impact of Environmental Exposures on Human Breast Milk Lipidome in Future Immune-Mediated Diseases. Environmental Science and Technology, 58(5), 2214-2223
Open this publication in new window or tab >>Impact of Environmental Exposures on Human Breast Milk Lipidome in Future Immune-Mediated Diseases
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2024 (English)In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 58, no 5, p. 2214-2223Article in journal (Refereed) Published
Abstract [en]

The composition of human breast milk (HBM) exhibits significant variability both between individuals and within the same individual. While environmental factors are believed to play a role in this variation, their influence on breast milk composition remains inadequately understood. Herein, we investigate the impact of environmental factors on HBM lipid composition in a general population cohort. The study included mothers (All Babies In Southeast Sweden study) whose children later progressed to one or more immune-mediated diseases later in life: type 1 diabetes (n = 9), celiac disease (n = 24), juvenile idiopathic arthritis (n = 9), inflammatory bowel disease (n = 7), hypothyroidism (n = 6), and matched controls (n = 173). Lipidome of HBM was characterized by liquid chromatography combined with high-resolution mass spectrometry. We observed that maternal age, body mass index, diet, and exposure to perfluorinated alkyl substances (PFASs) had a marked impact on breast milk lipidome, with larger changes observed in the milk of those mothers whose children later developed autoimmune diseases. We also observed differences in breast milk lipid composition in those mothers whose offspring later developed autoimmune diseases. Our study suggests that breast milk lipid composition is modified by a complex interaction between genetic and environmental factors, and, importantly, this impact was significantly more pronounced in those mothers whose offspring later developed autoimmune/inflammatory diseases. Our findings also suggest that merely assessing PFAS concentration may not capture the full extent of the impact of chemical exposures; thus, the more comprehensive exposome approach is essential for accurately assessing the impact of PFAS exposure on HBM and, consequently, on the health outcomes of the offspring.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2024
Keywords
Autoimmune diseases, human breast milk, lipidomics, maternal factors, perfluorinated alkyl substances
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:oru:diva-111048 (URN)10.1021/acs.est.3c06269 (DOI)001158427900001 ()38263945 (PubMedID)2-s2.0-85184299972 (Scopus ID)
Funder
Swedish Research Council, 2020-03674; 2016-05176; K2005-72X-11242-11A; K2008-69X-20826-01-4; K2008-69X-20826-01-4Swedish Research Council Formas, 2019-00869Novo Nordisk, NNF20OC0063971; NNF21OC0070309Swedish Child Diabetes FoundationForte, Swedish Research Council for Health, Working Life and Welfare, FAS2004-1775; FAS2004-1775Medical Research Council of Southeast Sweden (FORSS)Wallenberg Foundations, K 98-99D-12813-01Region ÖstergötlandLinköpings universitet
Note

This study was supported by the Swedish Research Council (grant nos. and 2020-03674 and 2016-05176 to T.H. and M.O.), Formas (grant no. 2019-00869 to T.H. and M.O.), and the Novo Nordisk Foundation (grant nos. NNF20OC0063971 and NNF21OC0070309 to T.H. and M.O.). ABIS study (J.L.) was supported by Barndiabetesfonden (Swedish Child Diabetes Foundation); the Swedish Council for Working Life and Social Research, grant/award numbers: FAS2004-1775 and FAS2004-1775; the Swedish Research Council, grant/award numbers: K2005-72X-11242-11A, K2008-69X-20826-01-4, and K2008-69X-20826-01-4; Östgöta Brandstodsbolag; the Medical Research Council of Southeast Sweden (FORSS); the Wallenberg Foundation, grant/award number: K 98-99D-12813-01A; ALF-and LFoU grants from Region Östergötland and Linköping university, Sweden; and Joanna Cocozza Foundation.

Available from: 2024-01-31 Created: 2024-01-31 Last updated: 2024-02-20Bibliographically approved
Hyötyläinen, T., McGlinchey, A. J., Salihovic, S., Schubert, A., Douglas, A., Hay, D. C., . . . Oresic, M. (2024). In utero exposures to perfluoroalkyl substances and the human fetal liver metabolome in Scotland: a cross-sectional study. The Lancet Planetary Health, 8(1), e5-e17
Open this publication in new window or tab >>In utero exposures to perfluoroalkyl substances and the human fetal liver metabolome in Scotland: a cross-sectional study
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2024 (English)In: The Lancet Planetary Health, E-ISSN 2542-5196, Vol. 8, no 1, p. e5-e17Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Perfluoroalkyl and polyfluoroalkyl substances are classed as endocrine disrupting compounds but continue to be used in many products such as firefighting foams, flame retardants, utensil coatings, and waterproofing of food packaging. Perfluoroalkyl exposure aberrantly modulates lipid, metabolite, and bile acid levels, increasing susceptibility to onset and severity of metabolic diseases, such as diabetes and metabolic dysfunction-associated steatotic liver disease. To date, most studies in humans have focused on perfluoroalkyl-exposure effects in adults. In this study we aimed to show if perfluoroalkyls are present in the human fetal liver and if they have metabolic consequences for the human fetus.

METHODS: In this cross-sectional study, human fetal livers from elective termination of pregnancies at the Aberdeen Pregnancy Counselling Service, Aberdeen, UK, were analysed by both targeted (bile acids and perfluoroalkyl substances) and combined targeted and untargeted (lipids and polar metabolites) mass spectrometry based metabolomic analyses, as well as with RNA-Seq. Only fetuses from normally progressing pregnancies (determined at ultrasound scan before termination), terminated for non-medical reasons, from women older than 16 years, fluent in English, and between 11 and 21 weeks of gestation were collected. Women exhibiting considerable emotional distress or whose fetuses had anomalies identified at ultrasound scan were excluded. Stringent bioinformatic and statistical methods such as partial correlation network analysis, linear regression, and pathway analysis were applied to this data to investigate the association of perfluoroalkyl exposure with hepatic metabolic pathways.

FINDINGS: Fetuses included in this study were collected between Dec 2, 2004, and Oct 27, 2014. 78 fetuses were included in the study: all 78 fetuses were included in the metabolomics analysis (40 female and 38 male) and 57 fetuses were included in the RNA-Seq analysis (28 female and 29 male). Metabolites associated with perfluoroalkyl were identified in the fetal liver and these varied with gestational age. Conjugated bile acids were markedly positively associated with fetal age. 23 amino acids, fatty acids, and sugar derivatives in fetal livers were inversely associated with perfluoroalkyl exposure, and the bile acid glycolithocholic acid was markedly positively associated with all quantified perfluoroalkyl. Furthermore, 7α-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis rate, was strongly positively associated with perfluoroalkyl levels and was detectable as early as gestational week 12.

INTERPRETATION: Our study shows direct evidence for the in utero effects of perfluoroalkyl exposure on specific key hepatic products. Our results provide evidence that perfluoroalkyl exposure, with potential future consequences, manifests in the human fetus as early as the first trimester of gestation. Furthermore, the profiles of metabolic changes resemble those observed in perinatal perfluoroalkyl exposures. Such exposures are already linked with susceptibility, initiation, progression, and exacerbation of a wide range of metabolic diseases.

Place, publisher, year, edition, pages
Elsevier, 2024
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:oru:diva-110658 (URN)10.1016/S2542-5196(23)00257-7 (DOI)001158718400001 ()38199723 (PubMedID)2-s2.0-85181938990 (Scopus ID)
Funder
EU, Horizon EuropeEU, FP7, Seventh Framework ProgrammeSwedish Research CouncilSwedish Research Council FormasNovo Nordisk FoundationAcademy of Finland
Note

FUNDING: UK Medical Research Council, Horizon Europe Program of the European Union, Seventh Framework Programme of the European Union, NHS Grampian Endowments grants, European Partnership for the Assessment of Risks from Chemicals, Swedish Research Council, Formas, Novo Nordisk Foundation, and the Academy of Finland.

Available from: 2024-01-11 Created: 2024-01-11 Last updated: 2024-02-20Bibliographically approved
Karlsson, J., Lopez-Sanchez, P., Marques, T. M., Hyötyläinen, T., Castro Alves, V., Krona, A. & Ström, A. (2024). Physico-chemical properties of pea fibre and pea protein blends and the implications for in vitro batch fermentation using human inoculum. Food Hydrocolloids, 150, Article ID 109732.
Open this publication in new window or tab >>Physico-chemical properties of pea fibre and pea protein blends and the implications for in vitro batch fermentation using human inoculum
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2024 (English)In: Food Hydrocolloids, ISSN 0268-005X, E-ISSN 1873-7137, Vol. 150, article id 109732Article in journal (Refereed) Published
Abstract [en]

The incorporation of fibre into pea protein matrices influences their microstructure, yet our understanding of their gut fermentability remains unexplored. In this study, dietary fibres and protein from yellow pea were investigated for their physico-chemical properties and impact on in vitro colonic fermentation using human inoculum. Pea fibre and pea protein blends were studied at different pH and after thermal treatment at 95 ◦C for 30 min with oscillatory rheology, static light scattering and confocal laser scanning microscopy. The effect on in vitro colonic fermentation was evaluated measuring gas production, ammonia, and short chain fatty acid (SCFA) production. Rheology indicated that during thermal treatment a firmer gel is formed close to the protein isoelectric point with a structure characterised by aggregation, but less particle swelling compared to other pH. Addition of fibre led to higher storage modulus (G′), with the fibre dominating the rheological properties. Fermentation of samples containing protein led to higher levels of ammonia and SCFA compared to only fibres. Blends produced higher amounts of valerate, i-valerate and caproate, and lower amounts of ammonia. Reduced fermentation of proteins in the presence of fibres was also reflected in a more intact microstructure of the protein particles in the digesta. Although thermal treatment of blends caused particle swelling and induced gelation, only small differences could be discerned in the in vitro colonic fermentation outcomes. Our results highlight that potentially harmful fermentation products from protein, such as ammonia, were reduced in the presence of pea hull fibre.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Yellow pea, Pea hull fibre, Pea protein, Rheology, Microstructure, In vitro human colonic fermentation
National Category
Food Science Chemical Sciences
Identifiers
urn:nbn:se:oru:diva-110717 (URN)10.1016/j.foodhyd.2024.109732 (DOI)2-s2.0-85181936389 (Scopus ID)
Funder
Swedish Research Council Formas, 2020-02843
Available from: 2024-01-16 Created: 2024-01-16 Last updated: 2024-01-16Bibliographically approved
Alijagic, A., Scherbak, N., Kotlyar, O., Karlsson, P., Wang, X., Odnevall, I., . . . Engwall, M. (2023). A Novel Nanosafety Approach Using Cell Painting, Metabolomics, and Lipidomics Captures the Cellular and Molecular Phenotypes Induced by the Unintentionally Formed Metal-Based (Nano)Particles. Cells, 12(2), Article ID 281.
Open this publication in new window or tab >>A Novel Nanosafety Approach Using Cell Painting, Metabolomics, and Lipidomics Captures the Cellular and Molecular Phenotypes Induced by the Unintentionally Formed Metal-Based (Nano)Particles
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2023 (English)In: Cells, E-ISSN 2073-4409, Vol. 12, no 2, article id 281Article in journal (Refereed) Published
Abstract [en]

Additive manufacturing (AM) or industrial 3D printing uses cutting-edge technologies and materials to produce a variety of complex products. However, the effects of the unintentionally emitted AM (nano)particles (AMPs) on human cells following inhalation, require further investigations. The physicochemical characterization of the AMPs, extracted from the filter of a Laser Powder Bed Fusion (L-PBF) 3D printer of iron-based materials, disclosed their complexity, in terms of size, shape, and chemistry. Cell Painting, a high-content screening (HCS) assay, was used to detect the subtle morphological changes elicited by the AMPs at the single cell resolution. The profiling of the cell morphological phenotypes, disclosed prominent concentration-dependent effects on the cytoskeleton, mitochondria, and the membranous structures of the cell. Furthermore, lipidomics confirmed that the AMPs induced the extensive membrane remodeling in the lung epithelial and macrophage co-culture cell model. To further elucidate the biological mechanisms of action, the targeted metabolomics unveiled several inflammation-related metabolites regulating the cell response to the AMP exposure. Overall, the AMP exposure led to the internalization, oxidative stress, cytoskeleton disruption, mitochondrial activation, membrane remodeling, and metabolic reprogramming of the lung epithelial cells and macrophages. We propose the approach of integrating Cell Painting with metabolomics and lipidomics, as an advanced nanosafety methodology, increasing the ability to capture the cellular and molecular phenotypes and the relevant biological mechanisms to the (nano)particle exposure.

Place, publisher, year, edition, pages
MDPI, 2023
Keywords
Additive manufacturing, high-content screening (HCS), inflammation, multivariate analysis, nanoparticle emissions, new approach methodologies (NAMs), targeted metabolomics
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:oru:diva-103319 (URN)10.3390/cells12020281 (DOI)000916977400001 ()36672217 (PubMedID)2-s2.0-85146736511 (Scopus ID)
Note

Funding agency:

General Electric 20190107 20160019

Available from: 2023-01-23 Created: 2023-01-23 Last updated: 2023-02-14Bibliographically approved
Hylén, U., Särndahl, E., Bejerot, S., Humble, M. B., Hyötyläinen, T., Salihovic, S. & Eklund, D. (2023). Alterations in inflammasome-related immunometabolites in individuals with severe psychiatric disorders. BMC Psychiatry, 23(1), Article ID 268.
Open this publication in new window or tab >>Alterations in inflammasome-related immunometabolites in individuals with severe psychiatric disorders
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2023 (English)In: BMC Psychiatry, E-ISSN 1471-244X, Vol. 23, no 1, article id 268Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Psychiatric disorders are common and significantly impact the quality of life. Inflammatory processes are proposed to contribute to the emergence of psychiatric disorders. In addition to inflammation, disturbances in metabolic pathways have been observed in individuals with different psychiatric disorders. A suggested key player in the interaction between inflammation and metabolism is the Nod-like receptor 3 (NLRP3) inflammasome, and NLRP3 is known to react to a number of specific metabolites. However, little is known about the interplay between these immunometabolites and the NLRP3 inflammasome in mental health disorders.

AIM: To assess the interplay between immunometabolites and inflammasome function in a transdiagnostic cohort of individuals with severe mental disorders.

METHODS: Mass spectrometry-based analysis of selected immunometabolites, previously known to affect inflammasome function, were performed in plasma from low-functioning individuals with severe mental disorders (n = 39) and sex and aged-matched healthy controls (n = 39) using a transdiagnostic approach. Mann Whitney U test was used to test differences in immunometabolites between psychiatric patients and controls. To assess the relationship between inflammasome parameters, disease severity, and the immunometabolites, Spearman's rank-order correlation test was used. Conditional logistic regression was used to control for potential confounding variables. Principal component analysis was performed to explore immunometabolic patterns.

RESULTS: Among the selected immunometabolites (n = 9), serine, glutamine, and lactic acid were significantly higher in the patient group compared to the controls. After adjusting for confounders, the differences remained significant for all three immunometabolites. No significant correlations were found between immunometabolites and disease severity.

CONCLUSION: Previous research on metabolic changes in mental disorders has not been conclusive. This study shows that severely ill patients have common metabolic perturbations. The changes in serine, glutamine, and lactic acid could constitute a direct contribution to the low-grade inflammation observed in severe psychiatric disorders.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
Comorbidity, Inflammasomes, Inflammation, Mental Disorders, Metabolic pathways, Psychoneuroimmunology
National Category
Psychiatry
Identifiers
urn:nbn:se:oru:diva-105613 (URN)10.1186/s12888-023-04784-y (DOI)000975250300004 ()37076825 (PubMedID)2-s2.0-85152978734 (Scopus ID)
Funder
Knowledge Foundation, 20200017
Available from: 2023-04-21 Created: 2023-04-21 Last updated: 2024-02-23Bibliographically approved
Herzig, M., Hyötyläinen, T., Vettese, G. F., Law, G. T. W., Vierinen, T. & Bomberg, M. (2023). Altering environmental conditions induce shifts in simulated deep terrestrial subsurface bacterial communities-Secretion of primary and secondary metabolites. Environmental Microbiology
Open this publication in new window or tab >>Altering environmental conditions induce shifts in simulated deep terrestrial subsurface bacterial communities-Secretion of primary and secondary metabolites
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2023 (English)In: Environmental Microbiology, ISSN 1462-2912, E-ISSN 1462-2920Article in journal (Refereed) Epub ahead of print
Abstract [en]

The deep terrestrial subsurface (DTS) harbours a striking diversity of microorganisms. However, systematic research on microbial metabolism, and how varying groundwater composition affects the bacterial communities and metabolites in these environments is lacking. In this study, DTS groundwater bacterial consortia from two Fennoscandian Shield sites were enriched and studied. We found that the enriched communities from the two sites consisted of distinct bacterial taxa, and alterations in the growth medium composition induced changes in cell counts. The lack of an exogenous organic carbon source (ECS) caused a notable increase in lipid metabolism in one community, while in the other, carbon starvation resulted in low overall metabolism, suggesting a dormant state. ECS supplementation increased CO2 production and SO4 2- utilisation, suggesting activation of a dissimilatory sulphate reduction pathway and sulphate-reducer-dominated total metabolism. However, both communities shared common universal metabolic features, most probably involving pathways needed for the maintenance of cell homeostasis (e.g., mevalonic acid pathway). Collectively, our findings indicate that the most important metabolites related to microbial reactions under varying growth conditions in enriched DTS communities include, but are not limited to, those linked to cell homeostasis, osmoregulation, lipid biosynthesis and degradation, dissimilatory sulphate reduction and isoprenoid production.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
National Category
Microbiology
Identifiers
urn:nbn:se:oru:diva-110378 (URN)10.1111/1462-2920.16552 (DOI)001124565200001 ()38098179 (PubMedID)2-s2.0-85180175195 (Scopus ID)
Note

Funding Agency:

Finnish Research Programme on Nuclear Waste Management KYT2022

Available from: 2023-12-19 Created: 2023-12-19 Last updated: 2024-02-05Bibliographically approved
Laudette, M., Lindbom, M., Arif, M., Cinato, M., Ruiz, M., Doran, S., . . . Borén, J. (2023). Cardiomyocyte-specific PCSK9 deficiency compromises mitochondrial bioenergetics and heart function. Cardiovascular Research, 119(7), 1537-1552
Open this publication in new window or tab >>Cardiomyocyte-specific PCSK9 deficiency compromises mitochondrial bioenergetics and heart function
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2023 (English)In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 119, no 7, p. 1537-1552Article in journal (Refereed) Published
Abstract [en]

AIMS: PCSK9, which is expressed mainly in the liver and at low levels in the heart, regulates cholesterol levels by directing low-density lipoprotein receptors to degradation. Studies to determine the role of PCSK9 in the heart are complicated by the close link between cardiac function and systemic lipid metabolism. Here, we sought to elucidate the function of PCSK9 specifically in the heart by generating and analysing mice with cardiomyocyte-specific Pcsk9 deficiency (CM-Pcsk9-/- mice) and by silencing Pcsk9 acutely in a cell culture model of adult cardiomyocyte-like cells.

METHODS AND RESULTS: Mice with cardiomyocyte-specific deletion of Pcsk9 had reduced contractile capacity, impaired cardiac function and left ventricular dilatation at 28 weeks of age and died prematurely. Transcriptomic analyses revealed alterations of signalling pathways linked to cardiomyopathy and energy metabolism in hearts from CM-Pcsk9-/- mice versus wildtype littermates. In agreement, levels of genes and proteins involved in mitochondrial metabolism were reduced in CM-Pcsk9-/- hearts. By using a Seahorse flux analyser, we showed that mitochondrial but not glycolytic function was impaired in cardiomyocytes from CM-Pcsk9-/- mice. We further showed that assembly and activity of electron transport chain (ETC) complexes were altered in isolated mitochondria from CM-Pcsk9-/- mice. Circulating lipid levels were unchanged in CM-Pcsk9-/- mice, but the lipid composition of mitochondrial membranes was altered. In addition, cardiomyocytes from CM-Pcsk9-/- mice had an increased number of mitochondria-ER contacts and alterations in the morphology of cristae, the physical location of the ETC complexes. We also showed that acute Pcsk9 silencing in adult cardiomyocyte-like cells reduced the activity of ETC complexes and impaired mitochondrial metabolism.

CONCLUSION: PCSK9, despite its low expression in cardiomyocytes, contributes to cardiac metabolic function, and PCSK9 deficiency in cardiomyocytes is linked to cardiomyopathy, impaired heart function, and compromised energy production.

TRANSLATIONAL PERSPECTIVE: PCSK9 is mainly present in the circulation where it regulates plasma cholesterol levels. Here we show that PCSK9 mediates intracellular functions that differ from its extracellular functions. We further show that intracellular PCSK9 in cardiomyocytes, despite low expression levels, is important for maintaining physiological cardiac metabolism and function.

Place, publisher, year, edition, pages
Oxford University Press, 2023
Keywords
Pro-protein convertase subtilisin-kexin type 9 (PCSK9), cardiac dysfunction, cardiomyocyte, metabolic inflexibility, mitochondria
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:oru:diva-104809 (URN)10.1093/cvr/cvad041 (DOI)000950475500001 ()36880401 (PubMedID)2-s2.0-85165884933 (Scopus ID)
Funder
Swedish Research CouncilSwedish Heart Lung Foundation
Available from: 2023-03-08 Created: 2023-03-08 Last updated: 2023-12-08Bibliographically approved
Lamichhane, S., Sen, P., Dickens, A. M., Kråkström, M., Ilonen, J., Lempainen, J., . . . Oresic, M. (2023). Circulating metabolic signatures of rapid and slow progression to type 1 diabetes in islet autoantibody-positive children. Frontiers in Endocrinology, 14, Article ID 1211015.
Open this publication in new window or tab >>Circulating metabolic signatures of rapid and slow progression to type 1 diabetes in islet autoantibody-positive children
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2023 (English)In: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 14, article id 1211015Article in journal (Refereed) Published
Abstract [en]

AIMS/HYPOTHESIS: Appearance of multiple islet cell autoantibodies in early life is indicative of future progression to overt type 1 diabetes, however, at varying rates. Here, we aimed to study whether distinct metabolic patterns could be identified in rapid progressors (RP, disease manifestation within 18 months after the initial seroconversion to autoantibody positivity) vs. slow progressors (SP, disease manifestation at 60 months or later from the appearance of the first autoantibody).

METHODS: Longitudinal samples were collected from RP (n=25) and SP (n=41) groups at the ages of 3, 6, 12, 18, 24, or ≥ 36 months. We performed a comprehensive metabolomics study, analyzing both polar metabolites and lipids. The sample series included a total of 239 samples for lipidomics and 213 for polar metabolites.

RESULTS: We observed that metabolites mediated by gut microbiome, such as those involved in tryptophan metabolism, were the main discriminators between RP and SP. The study identified specific circulating molecules and pathways, including amino acid (threonine), sugar derivatives (hexose), and quinic acid that may define rapid vs. slow progression to type 1 diabetes. However, the circulating lipidome did not appear to play a major role in differentiating between RP and SP.

CONCLUSION/INTERPRETATION: Our study suggests that a distinct metabolic profile is linked with the type 1 diabetes progression. The identification of specific metabolites and pathways that differentiate RP from SP may have implications for early intervention strategies to delay the development of type 1 diabetes.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
Birth cohort, gut microbial metabolites, lipidomics, metabolomics, type 1 diabetes mellitus
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:oru:diva-108526 (URN)10.3389/fendo.2023.1211015 (DOI)001067529600001 ()37745723 (PubMedID)2-s2.0-85171890067 (Scopus ID)
Funder
Novo Nordisk Foundation, NNF18OC0034506Academy of Finland, 250114 323171 333981 337530
Note

This study was supported by the Novo Nordisk Foundation (NNF18OC0034506, to MO), Juvenile Diabetes Research Foundation (2-SRA-2014-159-Q-R, to MO, TH, RL, and MKn), Academy of Finland (Centre of Excellence in Molecular Systems Immunology and Physiology Research – SyMMyS, Decision No. 250114, to RL, JT, MO, RL, and MKn; and Personalised Health 2014 programme project, Decision No. 292568, to RL, JT, MO, RL, and MKn). Further support was received by the Academy of Finland postdoctoral grant (No. 323171 to SL) and (grant no. 333981 to MO), “Inflammation in human early life: targeting impacts on life-course health” (INITIALISE) consortium funded by the Horizon Europe Program of the European Union under Grant Agreement 101094099 (to MO), the Medical Research Funds, Tampere and Helsinki University Hospitals (to MKn), InFLAMES Flagship Programme of the Academy of Finland (decision number: 337530) and Turku University Hospital (to MO, RL, and JT).

Available from: 2023-09-25 Created: 2023-09-25 Last updated: 2024-01-31Bibliographically approved
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