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| 2. |
- Govaere, O., et al.
(författare)
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Macrophage scavenger receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease
- 2022
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Ingår i: Journal of Hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 76:5, s. 1001-1012
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the role of macrophage scavenger receptor 1 (MSR1, CD204) remains incompletely understood. Methods: A total of 170 NAFLD liver biopsies were processed for transcriptomic analysis and correlated with clinicopathological features. Msr1-/- and wild-type mice were subjected to a 16-week high-fat and high-cholesterol diet. Mice and ex vivo human liver slices were treated with a monoclonal antibody against MSR1. Genetic susceptibility was assessed using genome-wide association study data from 1,483 patients with NAFLD and 430,101 participants of the UK Biobank. Results: MSR1 expression was associated with the occurrence of hepatic lipid-laden foamy macrophages and correlated with the degree of steatosis and steatohepatitis in patients with NAFLD. Mice lacking Msr1 were protected against diet-induced metabolic disorder, showing fewer hepatic foamy macrophages, less hepatic inflammation, improved dyslipidaemia and glucose tolerance, and altered hepatic lipid metabolism. Upon induction by saturated fatty acids, MSR1 induced a pro-inflammatory response via the JNK signalling pathway. In vitro blockade of the receptor prevented the accumulation of lipids in primary macrophages which inhibited the switch towards a pro-inflammatory phenotype and the release of cytokines such as TNF-ɑ. Targeting MSR1 using monoclonal antibody therapy in an obesity-associated NAFLD mouse model and human liver slices resulted in the prevention of foamy macrophage formation and inflammation. Moreover, we identified that rs41505344, a polymorphism in the upstream transcriptional region of MSR1, was associated with altered serum triglycerides and aspartate aminotransferase levels in a cohort of over 400,000 patients. Conclusions: Taken together, our data suggest that MSR1 plays a critical role in lipid-induced inflammation and could thus be a potential therapeutic target for the treatment of NAFLD. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is a chronic disease primarily caused by excessive consumption of fat and sugar combined with a lack of exercise or a sedentary lifestyle. Herein, we show that the macrophage scavenger receptor MSR1, an innate immune receptor, mediates lipid uptake and accumulation in Kupffer cells, resulting in liver inflammation and thereby promoting the progression of NAFLD in humans and mice. © 2021 The Authors
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- Johnson, Katherine, et al.
(författare)
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Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression : Diagnostic and mechanistic relevance
- 2022
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Ingår i: JHEP Reports. - : Elsevier. - 2589-5559. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Serum microRNA (miRNA) levels are known to change in non-alcoholic fatty liver disease (NAFLD) and may serve as useful biomarkers. This study aimed to profile miRNAs comprehensively at all NAFLD stages.Methods: We profiled 2,083 serum miRNAs in a discovery cohort (183 cases with NAFLD representing the complete NAFLD spectrum and 10 population controls). miRNA libraries generated by HTG EdgeSeq were sequenced by Illumina NextSeq. Selected serum miRNAs were profiled in 372 additional cases with NAFLD and 15 population controls by quantitative reverse transcriptase PCR.Results: Levels of 275 miRNAs differed between cases and population controls. Fewer differences were seen within individual NAFLD stages, but miR-193a-5p consistently showed increased levels in all comparisons. Relative to NAFL/non-alcoholic steatohepatitis (NASH) with mild fibrosis (stage 0/1), 3 miRNAs (miR-193a-5p, miR-378d, and miR378d) were increased in cases with NASH and clinically significant fibrosis (stages 2-4), 7 (miR193a-5p, miR-378d, miR-378e, miR-320b, miR-320c, miR-320d, and miR-320e) increased in cases with NAFLD activity score (NAS) 5-8 compared with lower NAS, and 3 (miR-193a-5p, miR-378d, and miR-378e) increased but 1 (miR-19b-3p) decreased in steatosis, activity, and fibrosis (SAF) activity score 2-4 compared with lower SAF activity. The significant findings for miR-193a-5p were replicated in the additional cohort with NAFLD. Studies in Hep G2 cells showed that following palmitic acid treatment, miR-193a-5p expression decreased significantly. Gene targets for miR-193a-5p were investigated in liver RNAseq data for a case subgroup (n = 80); liver GPX8 levels correlated positively with serum miR-193a-5p.Conclusions: Serum miR-193a-5p levels correlate strongly with NAFLD activity grade and fibrosis stage. MiR-193a-5p may have a role in the hepatic response to oxidative stress and is a potential clinically tractable circulating biomarker for progressive NAFLD.Lay summary: MicroRNAs (miRNAs) are small pieces of nucleic acid that may turn expression of genes on or off. These molecules can be detected in the blood circulation, and their levels in blood may change in liver disease including non-alcoholic fatty liver disease (NAFLD). To see if we could detect specific miRNA associated with advanced stages of NAFLD, we carried out miRNA sequencing in a group of 183 patients with NAFLD of varying severity together with 10 population controls. We found that a number of miRNAs showed changes, mainly increases, in serum levels but that 1 particular miRNA miR-193a-5p consistently increased. We confirmed this increase in a second group of cases with NAFLD. Measuring this miRNA in a blood sample may be a useful way to determine whether a patient has advanced NAFLD without an invasive liver biopsy.
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- Anstee, Quentin M., et al.
(författare)
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Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically-characterised cohort
- 2020
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 73:3, s. 505-515
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Genetic factors associated with non-alcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most GWAS studies have adopted radiologically assessed hepatic triglyceride content as reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a genome-wide association study (GWAS) encompassing the full spectrum of histologically characterized NAFLD.METHODS: The GWAS involved 1483 European NAFLD cases and 17781 genetically-matched population controls. A replication cohort of 559 NAFLD cases and 945 controls was genotyped to confirm signals showing genome-wide or close to genome-wide significance.RESULTS: Case-control analysis identified signals showing p-values ≤ 5 x 10-8 at four locations (chromosome (chr) 2 GCKR/C2ORF16; chr4 HSD17B13; chr19 TM6SF2; chr22 PNPLA3) together with two other signals with p<1 x10-7 (chr1 near LEPR and chr8 near IDO2/TC1). Case-only analysis of quantitative traits steatosis, disease activity score, NAS and fibrosis showed that the PNPLA3 signal (rs738409) was genome-wide significantly associated with steatosis, fibrosis and NAS score and identified a new signal (PYGO1 rs62021874) with close to genome-wide significance for steatosis (p=8.2 x 10-8). Subgroup case-control analysis for NASH confirmed the PNPLA3 signal. The chr1 LEPR SNP also showed genome-wide significance for this phenotype. Considering the subgroup with advanced fibrosis (≥F3), the signals on chromosomes 2, 19 and 22 remained genome-wide significant. With the exception of GCKR/C2ORF16, the genome-wide significant signals replicated.CONCLUSIONS: This study confirms PNPLA3 as a risk factor for the full histological spectrum of NAFLD at genome-wide significance levels, with important contributions from TM6SF2 and HSD17B13. PYGO1 is a novel steatosis modifier, suggesting relevance of Wnt signalling pathways in NAFLD pathogenesis.
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| 16. |
- Chalandon, Y., et al.
(författare)
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Outcome of patients developing GVHD after DLI given to treat CML relapse: a study by the chronic leukemia working party of the EBMT
- 2010
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Ingår i: Bone Marrow Transplantation. - : Springer Science and Business Media LLC. - 1476-5365 .- 0268-3369. ; 45:3, s. 558-564
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Tidskriftsartikel (refereegranskat)abstract
- We studied GVHD after donor lymphocyte infusion (DLI) in 328 patients with relapsed CML between 1991 and 2004. A total of 122 patients (38%) developed some form of GVHD. We analyzed GVHD by clinical presentation (acute or chronic GVHD) and onset time after the first DLI (early (<= 45 days) or late (>45 days)). There was a significant overlap between onset time and clinical presentation. Some form of GVHD occurred at a median of 104 days, acute GVHD at 45 days and chronic GVHD at 181 days after DLI. The clinical presentation was acute GVHD in 71 patients, of whom 31 subsequently developed chronic GVHD subsequently. De novo chronic GVHD was seen in 51 patients. OS for all patients was 69% (95% confidence interval (CI) 63-75) at 5 years, DLI-related mortality was 11% (95% CI 8-15) and disease-related mortality was 20% (95% CI 16-25). Risk factors for developing GVHD after DLI were T-cell dose at first DLI, the time interval from transplant to DLI and donor type. In time-dependent multivariate analysis, GVHD after DLI was associated with a risk of death of 2.3-fold compared with patients without GVHD. Clinical presentation as acute GVHD and early onset GVHD were associated with increased mortality.
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| 18. |
- Govaere, Olivier, et al.
(författare)
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Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis
- 2020
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Ingår i: Science Translational Medicine. - Washington, DC, United States : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 12:572
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Tidskriftsartikel (refereegranskat)abstract
- The mechanisms that drive nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This large multicenter study characterized the transcriptional changes that occur in liver tissue across the NAFLD spectrum as disease progresses to cirrhosis to identify potential circulating markers. We performed high-throughput RNA sequencing on a discovery cohort comprising histologically characterized NAFLD samples from 206 patients. Unsupervised clustering stratified NAFLD on the basis of disease activity and fibrosis stage with differences in age, aspartate aminotransferase (AST), type 2 diabetes mellitus, and carriage of PNPLA3 rs738409, a genetic variant associated with NAFLD. Relative to early disease, we consistently identified 25 differentially expressed genes as fibrosing steatohepatitis progressed through stages F2 to F4. This 25-gene signature was independently validated by logistic modeling in a separate replication cohort (n = 175), and an integrative analysis with publicly available single-cell RNA sequencing data elucidated the likely relative contribution of specific intrahepatic cell populations. Translating these findings to the protein level, SomaScan analysis in more than 300 NAFLD serum samples confirmed that circulating concentrations of proteins AKR1B10 and GDF15 were strongly associated with disease activity and fibrosis stage. Supporting the biological plausibility of these data, in vitro functional studies determined that endoplasmic reticulum stress up-regulated expression of AKR1B10, GDF15, and PDGFA, whereas GDF15 supplementation tempered the inflammatory response in macrophages upon lipid loading and lipopolysaccharide stimulation. This study provides insights into the pathophysiology of progressive fibrosing steatohepatitis, and proof of principle that transcriptomic changes represent potentially tractable and clinically relevant markers of disease progression.
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| 25. |
- McGlinchey, Aidan J, 1984-, et al.
(författare)
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Metabolic signatures across the full spectrum of non-alcoholic fatty liver disease
- 2022
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Ingår i: JHEP Reports. - : Elsevier. - 2589-5559. ; 4:5
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease with potentially severe complications including cirrhosis and hepatocellular carcinoma. Previously, we have identified circulating lipid signatures associating with liver fat content and non-alcoholic steatohepatitis (NASH). Here, we develop a metabolomic map across the NAFLD spectrum, defining interconnected metabolic signatures of steatosis (non-alcoholic fatty liver, NASH, and fibrosis).Methods: We performed mass spectrometry analysis of molecular lipids and polar metabolites in serum samples from the European NAFLD Registry patients (n = 627), representing the full spectrum of NAFLD. Using various univariate, multivariate, and machine learning statistical approaches, we interrogated metabolites across 3 clinical perspectives: steatosis, NASH, and fibrosis.Results: Following generation of the NAFLD metabolic network, we identify 15 metabolites unique to steatosis, 18 to NASH, and 15 to fibrosis, with 27 common to all. We identified that progression from F2 to F3 fibrosis coincides with a key pathophysiological transition point in disease natural history, with n = 73 metabolites altered.Conclusions: Analysis of circulating metabolites provides important insights into the metabolic changes during NAFLD progression, revealing metabolic signatures across the NAFLD spectrum and features that are specific to NAFL, NASH, and fibrosis. The F2-F3 transition marks a critical metabolic transition point in NAFLD pathogenesis, with the data pointing to the pathophysiological importance of metabolic stress and specifically oxidative stress.Clinical Trials registration: The study is registered at Clinicaltrials.gov (NCT04442334).Lay summary: Non-alcoholic fatty liver disease is characterised by the build-up of fat in the liver, which progresses to liver dysfunction, scarring, and irreversible liver failure, and is markedly increasing in its prevalence worldwide. Here, we measured lipids and other small molecules (metabolites) in the blood with the aim of providing a comprehensive molecular overview of fat build-up, liver fibrosis, and diagnosed severity. We identify a key metabolic 'watershed' in the progression of liver damage, separating severe disease from mild, and show that specific lipid and metabolite profiles can help distinguish and/or define these cases.
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| 26. |
- Sen, Partho, 1983-, et al.
(författare)
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Quantitative modeling of human liver reveals dysregulation of glycosphingolipid pathways in nonalcoholic fatty liver disease
- 2022
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Ingår i: iScience. - : Cell Press. - 2589-0042. ; 25:9
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Tidskriftsartikel (refereegranskat)abstract
- Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent disease that is associated with multiple metabolic disturbances, yet the metabolic pathways underlying its progression are poorly understood. Here, we studied metabolic pathways of the human liver across the full histological spectrum of NAFLD. We analyzed whole liver tissue transcriptomics and serum metabolomics data obtained from a large, prospectively enrolled cohort of 206 histologically characterized patients derived from the European NAFLD Registry and developed genome-scale metabolic models (GEMs) of human hepatocytes at different stages of NAFLD. We identified several metabolic signatures in the liver and blood of these patients, specifically highlighting the alteration of vitamins (A, E) and glycosphingolipids, and their link with complex glycosaminoglycans in advanced fibrosis. Furthermore, we derived GEMs and identified metabolic signatures of three common NAFLD-associated gene variants (PNPLA3, TM6SF2, and HSD17B13). The study demonstrates dysregulated liver metabolic pathways which may contribute to the progression of NAFLD.
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| 27. |
- McGlinchey, Aidan J, 1984-, et al.
(författare)
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Metabolomics approaches to identify biomarkers of nonalcoholic fatty liver disease
- 2020
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 73:Suppl. 1, s. S438-S438
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is a progressive liver disease that is strongly associated with type 2 diabetes. Accurate, non-invasive diagnostic tests to deliniate the different stages: degree of steatosis, grade of nonalcoholic steatohepatitis (NASH) and stage fibrosis represent an unmet medical need. In our previous studies, we successfully identified specific serum molecular lipid signatures which associate with the amount of liver fat as well as with NASH. Here we report underlying associations between clinical data, lipidomic profiles, metabolic profiles and clinical outcomes, including downstream identification of potential biomarkers for various stages of the disease.Method: We leverage several statistical and machine-learning approaches to analyse clinical, lipidomic and metabolomic profiles of individuals from the European Horizon 2020 project: Elucidating Pathways of Steatohepatitis (EPoS). We interrogate data on patients representing the full spectrum of NAFLD/NASH derived from the EPoS European NAFLD Registry (n = 627). We condense the EPoS lipidomic data into lipid clusters and subsequently apply non-rejection-rate-pruned partial correlation network techniques to facilitate network analysis between the datasets of lipidomic, metabolomic and clinical data. For biomarker identification, random forest ensemble classification and neural network machine learning approaches were used to both search for valid disease biomarkers and to assess the relative improvement over clinical-data-only classification versus addition of our lipidomic and metabolomic datasets.Results: We found that steatosis grade was strongly associated with (1) an increase of triglycerides with low carbon number and double bond count as well as (2) a decrease of specific phospholipids, including lysophosphatidylcholines. In addition to the network topology as a result itself, we also present lipid clusters (LCs) of interest to the derived network of proposed interactions in our NAFLD data from the EPoS cohort, along with our proposed biomarkers for various disease outcomes, as put forward by our current machine learning analyses.Conclusion: Our findings suggest that dysregulation of lipid metabolism in progressive stages of NAFLD is reflected in circulation and may thus hold diagnostic value as well as offer new insights about the NAFLD pathogenesis. Using this cohort as a proof-of-concept, we demonstrate current progress in tuning the accuracy of neural network and random forest approaches with a view to predicting various subtypes of NAFLD patient using a minimal set of lipidomic and metabolic markers. A detailed network-based picture emerges between lipids, polar metabolites and clinical variables. Lipidomic/metabolomic markers may provide an alternative method of NAFLD patient classification and risk stratification to guide therapy.
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| 28. |
- McGlinchey, Aidan J, 1984-, et al.
(författare)
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The Metabolomics of Non-Alcoholic Fatty Liver Disease : Of Networks and Biomarkers
- 2021
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 75:Suppl. 2, s. S579-S580
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background and aims: Non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver disease, affects 25%+ of people worldwide. Detailed understanding of the metabolomics of NAFLD, and non-invasive diagnostic techniques for the stages of NAFLD are unavailable. We identify specific serum molecular lipid signatures to these ends.First, we leverage lipidomic and polar metabolomic data (n = 643) subjects, to produce a clear, meaningful interaction map, linking lipids, metabolites, clinical factors and disease outcomes. We find non-spurious associations therein, as features of interest, and for downstream analysis.Third, NAFLD fibrosis biomarker identification was performed using machine learning, with our candidate lipids/metabolites to be forwarded to a successor project; the LITMUS project, towards clinically-applicable, non-invasive, sensitive and specific classification of NAFLD patients.Method: Serum lipids and polar metabolites were measured by mass spectrometry in the EPoS cohort of patients (n = 176 lipids and n = 36 polar metabolites), combined with clinical data from (n = 643 subjects), followed by model-based clustering, giving 10 lipid clusters (LCs).Correlations were calculated pairwise between (1) all LCs, (2) “input” clinical data (height, weight, BMI, blood platelet count) and (3) outcomes (fibrosis, steatosis, NAS score, etc.). Non-rejection rates (NRRs) were calculated for relationships, remove spurious associations (NRR > 0.4). We project the remaining associations as a network; a novel metabolomic overview NAFLD.ANOVA and Tukey’s Honest Significant Differences (Tukey HSDs) revealed detailed metabolic signatures across NAFLD, fibrosis and steatosis stages.Random forest machine learning was used to classify NAFLD patients: LOW (0-1 fibrosis grade) or HIGH (2–4 fibrosis grade), using individual lipids and metabolites, identifying putative biomarkers.Results: In linewith our previous findings, many lipids associate with steatosis and fibrosis in NAFLD. Our novel overview network revealsas sociations between specific LCs and clinical variables, such as TGs (LC3), and a subgroup of TGs of lowest and highest carbon numbers (LC9) along with PC (O)s (LC7) positively associating with NAFLD score and fibrosis. Conversely, LPCs (LC4), particularly sphingomyelins (SMs, LC6), negatively associated with these variables. Many other metabolites changing across NAFLD stages beg further discussion.Conclusion: In addition to generation of a novel metabolomic network of NAFLD, we demonstrate feasibility of lipidomic and metabolomic data to classify NAFLD patients’fibrosis grades (median AUC: 0.765), competitive with gold-standard clinical variables (age, BMI, sex, diabetes, liver AST/ALT, platelet count) (median AUC: 0.778). These biomarkers are being taken forward (LITMUS project) to develop clinical testing.
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| 31. |
- Sen, Parho, et al.
(författare)
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Metabolism of human liver on a genome scale in non-alcoholic fatty liver disease
- 2020
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 73:Suppl. 1, s. S671-S672
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background and Aims: Non-alcoholic fatty liver disease (NAFLD) is a major risk factor leading to chronic liver disease and type 2 diabetes. By using patient-matched liver transcriptomics and serum metabolomics data from the EPoS European NAFLD Registry cohort, we conducted genome-scale metabolic modeling (GSMM) to dissect hepatic metabolism across the full spectrum of NAFLD, from steatosis (NAFL) to NASH-cirrhosis.Method: We compared the genome-scale metabolic networks across different stages of NAFLD together with healthy controls (HC, n = 10), with the patients divided into three groups: steatosis (n = 60), NASH (n = 139; F0: n = 4, F1 n = 28, F2: n = 53, F3: n = 54) and cirrhosis (n = 14). Based on transcriptomics data obtained from the liver biopsy of the patients enrolled in the European NAFLD Registry, genome-scale metabolic models of the liver were developed and contextualized for these conditions. GSMM, as a scaffold, connects metabolic genes (i.e., enzymes) and metabolic pathways. Moreover, genome-scale networks can be constrained with multi-‘omics’ datasets, and thus connect an organism’s genotype to phenotype.Results: GSMM revealed that similar metabolic functions are perturbed in NAFL and NASH, while additional metabolic processes were regulated in advanced fibrosis/cirrhosis. The primary liver processes such as glycerophospholipid metabolism, chondroitin/heparan sulfate, bile acid and fatty acid biosynthesis and oxidation (carnitine shuttle in mitochondria) were affected. Lipid precursors for VLDL particles were upregulated in NAFL. Integrative analysis of transcriptomics and serum metabolomics data also revealed that several microbial pathways are up-regulated in NAFLD and may contribute to pathogenesis.Conclusion: A GSMM approach has identified common and specific liver metabolic pathways across different stages of NAFLD progression. Data were cross-validated by serum metabolomics, where in addition analysis also revealed that specific microbially-produced metabolites are elevated in NAFLD as compared to controls. These results provide important insights into the changes in hepatic metabolism occurring during NAFLD/NASH pathogenesis.
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