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Luukkonen, P. K., Tukiainen, T., Juuti, A., Sammalkorpi, H., Haridas, P. A., Niemelä, O., . . . Yki-Järvinen, H. (2020). Hydroxysteroid 17-β dehydrogenase 13 variant increases phospholipids and protects against fibrosis in nonalcoholic fatty liver disease. JCI Insight, 5(5), Article ID 132158.
Open this publication in new window or tab >>Hydroxysteroid 17-β dehydrogenase 13 variant increases phospholipids and protects against fibrosis in nonalcoholic fatty liver disease
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2020 (English)In: JCI Insight, ISSN 2379-3708, Vol. 5, no 5, article id 132158Article in journal (Refereed) Published
Abstract [en]

Carriers of the hydroxysteroid 17-β dehydrogenase 13 (HSD17B13) gene variant (rs72613567:TA) have a reduced risk of NASH and cirrhosis but not steatosis. We determined its effect on liver histology, lipidome, and transcriptome using ultra performance liquid chromatography-mass spectrometry and RNA-seq. In carriers and noncarriers of the gene variant, we also measured pathways of hepatic fatty acids (de novo lipogenesis [DNL] and adipose tissue lipolysis [ATL] using 2H2O and 2H-glycerol) and insulin sensitivity using 3H-glucose and euglycemic-hyperinsulinemic clamp) and plasma cytokines. Carriers and noncarriers had similar age, sex and BMI. Fibrosis was significantly less frequent while phospholipids, but not other lipids, were enriched in the liver in carriers compared with noncarriers. Expression of 274 genes was altered in carriers compared with noncarriers, consisting predominantly of downregulated inflammation-related gene sets. Plasma IL-6 concentrations were lower, but DNL, ATL and hepatic insulin sensitivity were similar between the groups. In conclusion, carriers of the HSD17B13 variant have decreased fibrosis and expression of inflammation-related genes but increased phospholipids in the liver. These changes are not secondary to steatosis, DNL, ATL, or hepatic insulin sensitivity. The increase in phospholipids and decrease in fibrosis are opposite to features of choline-deficient models of liver disease and suggest HSD17B13 as an attractive therapeutic target.

Place, publisher, year, edition, pages
American Society for Clinical Investigation, 2020
Keywords
Fibrosis, Genetic variation, Hepatitis, Hepatology, Metabolism
National Category
Medical Genetics
Identifiers
urn:nbn:se:oru:diva-80607 (URN)10.1172/jci.insight.132158 (DOI)000519997400006 ()32161197 (PubMedID)
Funder
Novo Nordisk
Note

Funding Agencies:

Elucidating Pathways of Steatohepatitis consortium - Horizon 2020 Framework Program of the European Union 634413

Innovative Medicines Initiative 2 Joint Undertaking 777377

European Union (EU)

European Federation of Pharmaceutical Industries and Associations  

Academy of Finland

EVO  

Sigrid Juselius Foundation

Ministry of Education, Universities and Research  

Italian National Research Council

British Heart Foundation Senior Fellowship in Basic Science  FS/15/56/31645

Jalmari and Rauha Ahokas Foundation  

Paulo Foundation 

Available from: 2020-03-13 Created: 2020-03-13 Last updated: 2020-04-01Bibliographically approved
Thomas, I., Dickens, A. M., Posti, J. P., Mohammadian, M., Ledig, C., Takala, R. S. K., . . . Oresic, M. (2020). Integrative Analysis of Circulating Metabolite Profiles and Magnetic Resonance Imaging Metrics in Patients with Traumatic Brain Injury. International Journal of Molecular Sciences, 21(4), Article ID E1395.
Open this publication in new window or tab >>Integrative Analysis of Circulating Metabolite Profiles and Magnetic Resonance Imaging Metrics in Patients with Traumatic Brain Injury
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2020 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 21, no 4, article id E1395Article in journal (Refereed) Published
Abstract [en]

Recent evidence suggests that patients with traumatic brain injuries (TBIs) have a distinct circulating metabolic profile. However, it is unclear if this metabolomic profile corresponds to changes in brain morphology as observed by magnetic resonance imaging (MRI). The aim of this study was to explore how circulating serum metabolites, following TBI, relate to structural MRI (sMRI) findings. Serum samples were collected upon admission to the emergency department from patients suffering from acute TBI and metabolites were measured using mass spectrometry-based metabolomics. Most of these patients sustained a mild TBI. In the same patients, sMRIs were taken and volumetric data were extracted (138 metrics). From a pool of 203 eligible screened patients, 96 met the inclusion criteria for this study. Metabolites were summarized as eight clusters and sMRI data were reduced to 15 independent components (ICs). Partial correlation analysis showed that four metabolite clusters had significant associations with specific ICs, reflecting both the grey and white matter brain injury. Multiple machine learning approaches were then applied in order to investigate if circulating metabolites could distinguish between positive and negative sMRI findings. A logistic regression model was developed, comprised of two metabolic predictors (erythronic acid and myo-inositol), which, together with neurofilament light polypeptide (NF-L), discriminated positive and negative sMRI findings with an area under the curve of the receiver-operating characteristic of 0.85 (specificity = 0.89, sensitivity = 0.65). The results of this study show that metabolomic analysis of blood samples upon admission, either alone or in combination with protein biomarkers, can provide valuable information about the impact of TBI on brain structural changes.

Place, publisher, year, edition, pages
MDPI, 2020
Keywords
Blood biomarkers, magnetic resonance imaging, mass spectrometry, metabolomics, traumatic brain injury
National Category
Neurosciences
Identifiers
urn:nbn:se:oru:diva-80215 (URN)10.3390/ijms21041395 (DOI)32092929 (PubMedID)
Available from: 2020-02-27 Created: 2020-02-27 Last updated: 2020-03-02Bibliographically approved
Sen, P., Dickens, A. M., López-Bascón, M. A., Lindeman, T., Kemppainen, E., Lamichhane, S., . . . Oresic, M. (2020). Metabolic alterations in immune cells associate with progression to type 1 diabetes. Diabetologia
Open this publication in new window or tab >>Metabolic alterations in immune cells associate with progression to type 1 diabetes
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2020 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428Article in journal (Refereed) Epub ahead of print
Abstract [en]

AIMS/HYPOTHESIS: Previous metabolomics studies suggest that type 1 diabetes is preceded by specific metabolic disturbances. The aim of this study was to investigate whether distinct metabolic patterns occur in peripheral blood mononuclear cells (PBMCs) of children who later develop pancreatic beta cell autoimmunity or overt type 1 diabetes.

METHODS: In a longitudinal cohort setting, PBMC metabolomic analysis was applied in children who (1) progressed to type 1 diabetes (PT1D, n = 34), (2) seroconverted to ≥1 islet autoantibody without progressing to type 1 diabetes (P1Ab, n = 27) or (3) remained autoantibody negative during follow-up (CTRL, n = 10).

RESULTS: During the first year of life, levels of most lipids and polar metabolites were lower in the PT1D and P1Ab groups compared with the CTRL group. Pathway over-representation analysis suggested alanine, aspartate, glutamate, glycerophospholipid and sphingolipid metabolism were over-represented in PT1D. Genome-scale metabolic models of PBMCs during type 1 diabetes progression were developed by using publicly available transcriptomics data and constrained with metabolomics data from our study. Metabolic modelling confirmed altered ceramide pathways, known to play an important role in immune regulation, as specifically associated with type 1 diabetes progression.

CONCLUSIONS/INTERPRETATION: Our data suggest that systemic dysregulation of lipid metabolism, as observed in plasma, may impact the metabolism and function of immune cells during progression to overt type 1 diabetes.

DATA AVAILABILITY: The GEMs for PBMCs have been submitted to BioModels (www.ebi.ac.uk/biomodels/), under accession number MODEL1905270001. The metabolomics datasets and the clinical metadata generated in this study were submitted to MetaboLights (https://www.ebi.ac.uk/metabolights/), under accession number MTBLS1015.

Place, publisher, year, edition, pages
Springer, 2020
Keywords
Birth cohort, Ceramides, Genome-scale metabolic modelling, Lipidomics, Metabolomics, Peripheral blood mononuclear cells, Sphingolipid metabolism, Type 1 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:oru:diva-79927 (URN)10.1007/s00125-020-05107-6 (DOI)000516166400001 ()32043185 (PubMedID)
Funder
Novo Nordisk, NNF18OC0034506
Note

Funding Agencies:

Juvenile Diabetes Research Foundation 2-SRA-2014-159-Q-R

Academy of Finland 250114

Academy of Finland (Personalised Health 2014 programme project)  292568

FPU scholarship from the Spanish Ministry of Education, Culture and Sport  FPU15/02373

Available from: 2020-02-20 Created: 2020-02-20 Last updated: 2020-03-16Bibliographically approved
Vande Vyvere, T., De La Rosa, E., Wilms, G., Nieboer, D., Steyerberg, E., Maas, A. I. R., . . . CENTER-TBI, P. a. (2020). Prognostic Validation of the NINDS Common Data Elements for the Radiologic Reporting of Acute Traumatic Brain Injuries: A CENTER-TBI Study.. Journal of Neurotrauma
Open this publication in new window or tab >>Prognostic Validation of the NINDS Common Data Elements for the Radiologic Reporting of Acute Traumatic Brain Injuries: A CENTER-TBI Study.
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2020 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042Article in journal (Refereed) Epub ahead of print
Abstract [en]

The aim of this study is to investigate the prognostic value of using the National Institute of Neurological Disorders and Stroke (NINDS) standardized imaging-based pathoanatomic descriptors for the evaluation and reporting of acute traumatic brain injury (TBI) lesions. For a total of 3392 patients (2244 males and 1148 females, median age = 51 years) enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, we extracted 96 Common Data Elements (CDEs) from the structured reports, spanning all three levels of pathoanatomic information (i.e., 20 "basic," 60 "descriptive," and 16 "advanced" CDE variables per patient). Six-month clinical outcome scores were dichotomized into favorable (Glasgow Outcome Scale Extended [GOS-E] = 5-8) versus unfavorable (GOS-E = 1-4). Regularized logistic regression models were constructed and compared using the optimism-corrected area under the curve (AUC). An abnormality was reported for the majority of patients (64.51%). In 79.11% of those patients, there was at least one coexisting pathoanatomic lesion or associated finding. An increase in lesion severity, laterality, and volume was associated with more unfavorable outcomes. Compared with the full set of pathoanatomic descriptors (i.e., all three categories of information), reporting "basic" CDE information provides at least equal discrimination between patients with favorable versus unfavorable outcome (AUC = 0.8121 vs. 0.8155, respectively). Addition of a selected subset of "descriptive" detail to the basic CDEs could improve outcome prediction (AUC = 0.8248). Addition of "advanced" or "emerging/exploratory" information had minimal prognostic value. Our results show that the NINDS standardized-imaging based pathoanatomic descriptors can be used in large-scale studies and provide important insights into acute TBI lesion patterns. When used in clinical predictive models, they can provide excellent discrimination between patients with favorable and unfavorable 6-month outcomes. If further validated, our findings could support the development of structured and itemized templates in routine clinical radiology.

Place, publisher, year, edition, pages
Mary Ann Liebert, 2020
Keywords
Common Data Elements, computed tomography, structured reporting, traumatic brain injury
National Category
Neurology
Identifiers
urn:nbn:se:oru:diva-80216 (URN)10.1089/neu.2019.6710 (DOI)31813313 (PubMedID)
Available from: 2020-02-27 Created: 2020-02-27 Last updated: 2020-03-03Bibliographically approved
Steyerberg, E. W., Wiegers, E., Sewalt, C., Buki, A., Citerio, G., De Keyser, V., . . . CENTER-TBI, P. a. (2019). Case-mix, care pathways, and outcomes in patients with traumatic brain injury in CENTER-TBI: a European prospective, multicentre, longitudinal, cohort study. Lancet Neurology, 18(10), 923-934
Open this publication in new window or tab >>Case-mix, care pathways, and outcomes in patients with traumatic brain injury in CENTER-TBI: a European prospective, multicentre, longitudinal, cohort study
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2019 (English)In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 18, no 10, p. 923-934Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The burden of traumatic brain injury (TBI) poses a large public health and societal problem, but the characteristics of patients and their care pathways in Europe are poorly understood. We aimed to characterise patient case-mix, care pathways, and outcomes of TBI.

METHODS: CENTER-TBI is a Europe-based, observational cohort study, consisting of a core study and a registry. Inclusion criteria for the core study were a clinical diagnosis of TBI, presentation fewer than 24 h after injury, and an indication for CT. Patients were differentiated by care pathway and assigned to the emergency room (ER) stratum (patients who were discharged from an emergency room), admission stratum (patients who were admitted to a hospital ward), or intensive care unit (ICU) stratum (patients who were admitted to the ICU). Neuroimages and biospecimens were stored in repositories and outcome was assessed at 6 months after injury. We used the IMPACT core model for estimating the expected mortality and proportion with unfavourable Glasgow Outcome Scale Extended (GOSE) outcomes in patients with moderate or severe TBI (Glasgow Coma Scale [GCS] score ≤12). The core study was registered with ClinicalTrials.gov, number NCT02210221, and with Resource Identification Portal (RRID: SCR_015582).

FINDINGS: Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study and from 22 782 patients in the registry. In the core study, 848 (19%) patients were in the ER stratum, 1523 (34%) in the admission stratum, and 2138 (47%) in the ICU stratum. In the ICU stratum, 720 (36%) patients had mild TBI (GCS score 13-15). Compared with the core cohort, the registry had a higher proportion of patients in the ER (9839 [43%]) and admission (8571 [38%]) strata, with more than 95% of patients classified as having mild TBI. Patients in the core study were older than those in previous studies (median age 50 years [IQR 30-66], 1254 [28%] aged >65 years), 462 (11%) had serious comorbidities, 772 (18%) were taking anticoagulant or antiplatelet medication, and alcohol was contributory in 1054 (25%) TBIs. MRI and blood biomarker measurement enhanced characterisation of injury severity and type. Substantial inter-country differences existed in care pathways and practice. Incomplete recovery at 6 months (GOSE <8) was found in 207 (30%) patients in the ER stratum, 665 (53%) in the admission stratum, and 1547 (84%) in the ICU stratum. Among patients with moderate-to-severe TBI in the ICU stratum, 623 (55%) patients had unfavourable outcome at 6 months (GOSE <5), similar to the proportion predicted by the IMPACT prognostic model (observed to expected ratio 1·06 [95% CI 0·97-1·14]), but mortality was lower than expected (0·70 [0·62-0·76]).

INTERPRETATION: Patients with TBI who presented to European centres in the core study were older than were those in previous observational studies and often had comorbidities. Overall, most patients presented with mild TBI. The incomplete recovery of many patients should motivate precision medicine research and the identification of best practices to improve these outcomes.

FUNDING: European Union 7th Framework Programme, the Hannelore Kohl Stiftung, OneMind, and Integra LifeSciences Corporation.

Place, publisher, year, edition, pages
The Lancet Publishing Group, 2019
National Category
Neurology
Identifiers
urn:nbn:se:oru:diva-77193 (URN)10.1016/S1474-4422(19)30232-7 (DOI)000485784000017 ()31526754 (PubMedID)2-s2.0-85071987996 (Scopus ID)
Available from: 2019-10-11 Created: 2019-10-11 Last updated: 2020-02-14Bibliographically approved
Vande Vyvere, T., Wilms, G., Claes, L., Martin Leon, F., Nieboer, D., Verheyden, J., . . . European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI), I. a. (2019). Central versus Local Radiological Reading of Acute Computed Tomography Characteristics in Multi-Center Traumatic Brain Injury Research.. Journal of Neurotrauma, 36(7), 1080-1092
Open this publication in new window or tab >>Central versus Local Radiological Reading of Acute Computed Tomography Characteristics in Multi-Center Traumatic Brain Injury Research.
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2019 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 36, no 7, p. 1080-1092Article in journal (Refereed) Published
Abstract [en]

Observer variability in local radiological reading is a major concern in large-scale multi-center traumatic brain injury (TBI) studies. A central review process has been advocated to minimize this variability. The aim of this study is to compare central with local reading of TBI imaging datasets and to investigate the added value of central review. A total of 2050 admission computed tomography (CT) scans from subjects enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study were analyzed for seven main CT characteristics. Kappa statistics were used to calculate agreement between central and local evaluations and a center-specific analysis was performed. The McNemar test was used to detect whether discordances were significant. Central interobserver and intra-observer agreement was calculated in a subset of patients. Good agreement was found between central and local assessment for the presence or absence of structural pathology (CT+, CT-, κ = 0.73) and most CT characteristics (κ = 0.62 to 0.71), except for traumatic axonal injury lesions (κ = 0.37). Despite good kappa values, discordances were significant in four of seven CT characteristics (i.e., midline shift, contusion, traumatic subarachnoid hemorrhage, and cisternal compression; p = 0.0005). Central reviewers showed substantial to excellent interobserver and intra-observer agreement (κ = 0.73 to κ = 0.96), contrasted by considerable variability in local radiological reading. Compared with local evaluation, a central review process offers a more consistent radiological reading of acute CT characteristics in TBI. It generates reliable, reproducible data and should be recommended for use in multi-center TBI studies.

Place, publisher, year, edition, pages
Mary Ann Liebert, 2019
Keywords
Agreement, central radiology review, traumatic brain injury
National Category
Clinical Medicine Neurology
Identifiers
urn:nbn:se:oru:diva-76158 (URN)10.1089/neu.2018.6061 (DOI)000450729800001 ()30259789 (PubMedID)2-s2.0-85063277328 (Scopus ID)
Available from: 2019-09-06 Created: 2019-09-06 Last updated: 2019-11-15Bibliographically approved
Lamichhane, S., Kemppainen, E., Trošt, K., Siljander, H., Hyöty, H., Ilonen, J., . . . Oresic, M. (2019). Circulating metabolites in progression to islet autoimmunity and type 1 diabetes. Diabetologia, 62(12), 2287-2297
Open this publication in new window or tab >>Circulating metabolites in progression to islet autoimmunity and type 1 diabetes
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2019 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, no 12, p. 2287-2297Article in journal (Refereed) Published
Abstract [en]

AIMS/HYPOTHESIS: Metabolic dysregulation may precede the onset of type 1 diabetes. However, these metabolic disturbances and their specific role in disease initiation remain poorly understood. In this study, we examined whether children who progress to type 1 diabetes have a circulatory polar metabolite profile distinct from that of children who later progress to islet autoimmunity but not type 1 diabetes and a matched control group.

METHODS: We analysed polar metabolites from 415 longitudinal plasma samples in a prospective cohort of children in three study groups: those who progressed to type 1 diabetes; those who seroconverted to one islet autoantibody but not to type 1 diabetes; and an antibody-negative control group. Metabolites were measured using two-dimensional GC high-speed time of flight MS.

RESULTS: In early infancy, progression to type 1 diabetes was associated with downregulated amino acids, sugar derivatives and fatty acids, including catabolites of microbial origin, compared with the control group. Methionine remained persistently upregulated in those progressing to type 1 diabetes compared with the control group and those who seroconverted to one islet autoantibody. The appearance of islet autoantibodies was associated with decreased glutamic and aspartic acids.

CONCLUSIONS/INTERPRETATION: Our findings suggest that children who progress to type 1 diabetes have a unique metabolic profile, which is, however, altered with the appearance of islet autoantibodies. Our findings may assist with early prediction of the disease.

Place, publisher, year, edition, pages
Springer, 2019
Keywords
Beta cell autoimmunity, Metabolomics, Type 1 diabetes
National Category
Other Basic Medicine Endocrinology and Diabetes
Identifiers
urn:nbn:se:oru:diva-75892 (URN)10.1007/s00125-019-04980-0 (DOI)000500998600012 ()31444528 (PubMedID)2-s2.0-85070968581 (Scopus ID)
Note

Funding Agencies:

Juvenile Diabetes Research Foundation 4-1998-2744-1999-731 4-2001-4352-SRA-2014-159-Q-R

Special research funds for Oulu University Hospital in Finland  

Special research funds for Tampere University Hospital in Finland  

Special research funds for Turku University Hospital in Finland  

Academy of Finland 250114

Available from: 2019-08-26 Created: 2019-08-26 Last updated: 2019-12-19Bibliographically approved
Lamichhane, S., Ahonen, L., Dyrlund, T. S., Dickens, A. M., Siljander, H., Hyöty, H., . . . Oresic, M. (2019). Cord-Blood Lipidome in Progression to Islet Autoimmunity and Type 1 Diabetes. Biomolecules, 9(1), Article ID E33.
Open this publication in new window or tab >>Cord-Blood Lipidome in Progression to Islet Autoimmunity and Type 1 Diabetes
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2019 (English)In: Biomolecules, E-ISSN 2218-273X, Vol. 9, no 1, article id E33Article in journal (Refereed) Published
Abstract [en]

Previous studies suggest that children who progress to type 1 diabetes (T1D) later in life already have an altered serum lipid molecular profile at birth. Here, we compared cord blood lipidome across the three study groups: children who progressed to T1D (PT1D; n = 30), children who developed at least one islet autoantibody but did not progress to T1D during the follow-up (P1Ab; n = 33), and their age-matched controls (CTR; n = 38). We found that phospholipids, specifically sphingomyelins, were lower in T1D progressors when compared to P1Ab and the CTR. Cholesterol esters remained higher in PT1D when compared to other groups. A signature comprising five lipids was predictive of the risk of progression to T1D, with an area under the receiver operating characteristic curve (AUROC) of 0.83. Our findings provide further evidence that the lipidomic profiles of newborn infants who progress to T1D later in life are different from lipidomic profiles in P1Ab and CTR.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
Autoimmunity, cord blood, lipidomics, metabolomics, type 1 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:oru:diva-71853 (URN)10.3390/biom9010033 (DOI)000458051700033 ()30669674 (PubMedID)2-s2.0-85060365305 (Scopus ID)
Note

Funding Agencies:

JDRF  4-1998-274  4-1999-731 4-2001-435 

Special research funds for Oulu, Tampere and Turku University Hospitals in Finland  

Juvenile Diabetes Research Foundation  2-SRA-2014-159-Q-R 

Academy of Finland (Centre of Excellence in Molecular Systems Immunology and Physiology Research-SyMMyS)  250114 

Available from: 2019-02-12 Created: 2019-02-12 Last updated: 2019-06-19Bibliographically approved
van Essen, T. A., den Boogert, H. F., Cnossen, M. C., de Ruiter, G. C. W., Haitsma, I., Polinder, S., . . . CENTER-TBI, I. a. (2019). Correction to: Variation in neurosurgical management of traumatic brain injury. Acta Neurochirurgica, 161(3), 451-455
Open this publication in new window or tab >>Correction to: Variation in neurosurgical management of traumatic brain injury
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2019 (English)In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 161, no 3, p. 451-455Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Springer, 2019
National Category
Clinical Medicine Neurology Surgery
Identifiers
urn:nbn:se:oru:diva-76159 (URN)10.1007/s00701-019-03815-6 (DOI)000460607500003 ()30715604 (PubMedID)2-s2.0-85061403050 (Scopus ID)
Note

Correction to Variation in neurosurgical management of traumatic brain injury: a survey in 68 centers participating in the CENTER-TBI study (2019) Acta Neurochirurgica, 161 (3), pp. 435-449. The collaborator names are inverted.

Available from: 2019-09-06 Created: 2019-09-06 Last updated: 2019-11-15Bibliographically approved
Hernández-Alvarez, M. I., Sebastián, D., Vives, S., Ivanova, S., Bartoccioni, P., Kakimoto, P., . . . Zorzano, A. (2019). Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease. Cell, 177(4), 881-895.e17
Open this publication in new window or tab >>Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease
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2019 (English)In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 177, no 4, p. 881-895.e17Article in journal (Refereed) Published
Abstract [en]

Non-alcoholic fatty liver is the most common liver disease worldwide. Here, we show that the mitochondrial protein mitofusin 2 (Mfn2) protects against liver disease. Reduced Mfn2 expression was detected in liver biopsies from patients with non-alcoholic steatohepatitis (NASH). Moreover, reduced Mfn2 levels were detected in mouse models of steatosis or NASH, and its re-expression in a NASH mouse model ameliorated the disease. Liver-specific ablation of Mfn2 in mice provoked inflammation, triglyceride accumulation, fibrosis, and liver cancer. We demonstrate that Mfn2 binds phosphatidylserine (PS) and can specifically extract PS into membrane domains, favoring PS transfer to mitochondria and mitochondrial phosphatidylethanolamine (PE) synthesis. Consequently, hepatic Mfn2 deficiency reduces PS transfer and phospholipid synthesis, leading to endoplasmic reticulum (ER) stress and the development of a NASH-like phenotype and liver cancer. Ablation of Mfn2 in liver reveals that disruption of ER-mitochondrial PS transfer is a new mechanism involved in the development of liver disease.

Place, publisher, year, edition, pages
Cell Press, 2019
Keywords
MAMs, Mfn2, NASH, mitochondria, phosphatidylserine, phospholipid transfer
National Category
Gastroenterology and Hepatology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:oru:diva-74195 (URN)10.1016/j.cell.2019.04.010 (DOI)000466843000010 ()31051106 (PubMedID)2-s2.0-85064698279 (Scopus ID)
Note

Funding Agencies:

CONACYT, Mexico  

MICINN Spain  

Coordenacao de Aperfeicoamento do Pessoal de Nivel Superior (CAPES)  

MINECO  SAF201675246R 

Generalitat de Catalunya (ICREA Academia)  2014SGR48  2017SGR696 

INFLAMES (ISCIII) PIE-14/00045 

CIBERDEM, ISCIII, INTERREG IV-B-SUDOE-FEDER (DIOMED)  SOE1/P1/E178 

"la Caixa'' Foundation  

Miguel Servet tenure-track program from the Fondo de Investigacion Sanitaria  CP10/00438  CPII16/00008 

ERD  

MINECO through the Centres of Excellence Severo Ochoa Award  

CERCA Programme of the Generalitat de Catalunya 

Available from: 2019-05-13 Created: 2019-05-13 Last updated: 2019-06-19Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-2856-9165

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