| 1. |
|
|
| 2. |
|
|
| 3. |
- Anstee, Quentin M., et al.
(författare)
-
Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically-characterised cohort
- 2020
-
Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 73:3, s. 505-515
-
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.
|
|
| 4. |
- Armandi, Angelo, et al.
(författare)
-
Serum ferritin levels can predict long-term outcomes in patients with metabolic dysfunction-associated steatotic liver disease
- 2024
-
Ingår i: Gut. - : BMJ PUBLISHING GROUP. - 0017-5749 .- 1468-3288.
-
Tidskriftsartikel (refereegranskat)abstract
- Objective Hyperferritinaemia is associated with liver fibrosis severity in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but the longitudinal implications have not been thoroughly investigated. We assessed the role of serum ferritin in predicting long-term outcomes or death. Design We evaluated the relationship between baseline serum ferritin and longitudinal events in a multicentre cohort of 1342 patients. Four survival models considering ferritin with confounders or non-invasive scoring systems were applied with repeated five-fold cross-validation schema. Prediction performance was evaluated in terms of Harrell's C-index and its improvement by including ferritin as a covariate. Results Median follow-up time was 96 months. Liver-related events occurred in 7.7%, hepatocellular carcinoma in 1.9%, cardiovascular events in 10.9%, extrahepatic cancers in 8.3% and all-cause mortality in 5.8%. Hyperferritinaemia was associated with a 50% increased risk of liver-related events and 27% of all-cause mortality. A stepwise increase in baseline ferritin thresholds was associated with a statistical increase in C-index, ranging between 0.02 (lasso-penalised Cox regression) and 0.03 (ridge-penalised Cox regression); the risk of developing liver-related events mainly increased from threshold 215.5 mu g/L (median HR=1.71 and C-index=0.71) and the risk of overall mortality from threshold 272 mu g/L (median HR=1.49 and C-index=0.70). The inclusion of serum ferritin thresholds (215.5 mu g/L and 272 mu g/L) in predictive models increased the performance of Fibrosis-4 and Non-Alcoholic Fatty Liver Disease Fibrosis Score in the longitudinal risk assessment of liver-related events (C-indices>0.71) and overall mortality (C-indices>0.65). Conclusions This study supports the potential use of serum ferritin values for predicting the long-term prognosis of patients with MASLD.
|
|
| 5. |
- Boesch, Markus, et al.
(författare)
-
Adipose tissue macrophage dysfunction is associated with a breach of vascular integrity in NASH
- 2024
-
Ingår i: Journal of Hepatology. - 0168-8278 .- 1600-0641. ; 80:3, s. 397-408
-
Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: In non-alcoholic fatty liver disease (NAFLD), monocytes infiltrate visceral adipose tissue promoting local and hepatic inflammation. However, it remains unclear what drives inflammation and how the immune landscape in adipose tissue differs across the NAFLD severity spectrum. We aimed to assess adipose tissue macrophage (ATM) heterogeneity in a NAFLD cohort. Methods: Visceral adipose tissue macrophages from lean and obese patients, stratified by NAFLD phenotypes, underwent single-cell RNA sequencing. Adipose tissue vascular integrity and breaching was assessed on a protein level via immunohistochemistry and immunofluorescence to determine targets of interest. Results: We discovered multiple ATM populations, including resident vasculature-associated macrophages (ResVAMs) and distinct metabolically active macrophages (MMacs). Using trajectory analysis, we show that ResVAMs and MMacs are replenished by a common transitional macrophage (TransMac) subtype and that, during NASH, MMacs are not effectively replenished by TransMac precursors. We postulate an accessory role for MMacs and ResVAMs in protecting the adipose tissue vascular barrier, since they both interact with endothelial cells and localize around the vasculature. However, across the NAFLD severity spectrum, alterations occur in these subsets that parallel an adipose tissue vasculature breach characterized by albumin extravasation into the perivascular tissue. Conclusions: NAFLD-related macrophage dysfunction coincides with a loss of adipose tissue vascular integrity, providing a plausible mechanism by which tissue inflammation is perpetuated in adipose tissue and downstream in the liver. Impact and implications: Our study describes for the first time the myeloid cell landscape in human visceral adipose tissue at single-cell level within a cohort of well-characterized patients with non-alcoholic fatty liver disease. We report unique non-alcoholic steatohepatitis-specific transcriptional changes within metabolically active macrophages (MMacs) and resident vasculature-associated macrophages (ResVAMs) and we demonstrate their spatial location surrounding the vasculature. These dysfunctional transcriptional macrophage states coincided with the loss of adipose tissue vascular integrity, providing a plausible mechanism by which tissue inflammation is perpetuated in adipose tissue and downstream in the liver. Our study provides a theoretical basis for new therapeutic strategies to be directed towards reinstating the endogenous metabolic, homeostatic and cytoprotective functions of ResVAMs and MMacs, including their role in protecting vascular integrity.
|
|
| 6. |
- Govaere, Olivier, et al.
(författare)
-
A proteo-transcriptomic map of non-alcoholic fatty liver disease signatures
- 2023
-
Ingår i: Nature Metabolism. - : NATURE PORTFOLIO. - 2522-5812. ; 5:4, s. 572-578
-
Tidskriftsartikel (refereegranskat)abstract
- Govaere et al. integrate circulating protein data from more than 300 patients with non-alcoholic fatty liver disease (NAFLD) with transcriptomics and develop a non-invasive diagnostics tool to identify patients with at-risk NAFLD based on body mass index, type 2 diabetes status and four circulating proteins. Non-alcoholic fatty liver disease (NAFLD) is a common, progressive liver disease strongly associated with the metabolic syndrome. It is unclear how progression of NAFLD towards cirrhosis translates into systematic changes in circulating proteins. Here, we provide a detailed proteo-transcriptomic map of steatohepatitis and fibrosis during progressive NAFLD. In this multicentre proteomic study, we characterize 4,730 circulating proteins in 306 patients with histologically characterized NAFLD and integrate this with transcriptomic analysis in paired liver tissue. We identify circulating proteomic signatures for active steatohepatitis and advanced fibrosis, and correlate these with hepatic transcriptomics to develop a proteo-transcriptomic signature of 31 markers. Deconvolution of this signature by single-cell RNA sequencing reveals the hepatic cell types likely to contribute to proteomic changes with disease progression. As an exemplar of use as a non-invasive diagnostic, logistic regression establishes a composite model comprising four proteins (ADAMTSL2, AKR1B10, CFHR4 and TREM2), body mass index and type 2 diabetes mellitus status, to identify at-risk steatohepatitis.
|
|
| 7. |
- Govaere, Olivier, et al.
(författare)
-
Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis
- 2020
-
Ingår i: Science Translational Medicine. - Washington, DC, United States : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 12:572
-
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.
|
|
| 8. |
- Johnson, Katherine, et al.
(författare)
-
Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression : Diagnostic and mechanistic relevance
- 2022
-
Ingår i: JHEP Reports. - : Elsevier. - 2589-5559. ; 4:2
-
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.
|
|
| 9. |
- McGlinchey, Aidan J, 1984-, et al.
(författare)
-
Metabolic signatures across the full spectrum of non-alcoholic fatty liver disease
- 2022
-
Ingår i: JHEP Reports. - : Elsevier. - 2589-5559. ; 4:5
-
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.
|
|
| 10. |
- McGlinchey, Aidan J, 1984-, et al.
(författare)
-
Metabolomics approaches to identify biomarkers of nonalcoholic fatty liver disease
- 2020
-
Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 73:Suppl. 1, s. S438-S438
-
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.
|
|
| 11. |
- McGlinchey, Aidan J, 1984-, et al.
(författare)
-
The Metabolomics of Non-Alcoholic Fatty Liver Disease : Of Networks and Biomarkers
- 2021
-
Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 75:Suppl. 2, s. S579-S580
-
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.
|
|
| 12. |
- Sen, Partho, 1983-, et al.
(författare)
-
Genome-scale metabolic modeling of human hepatocytes reveals dysregulation of glycosphingolipid pathways in progressive non-alcoholic fatty liver disease
- 2021
-
Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 75:Suppl. 2, s. S256-S256
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background and aims: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of chronic liver diseases intertwined with the metabolic disorders. The prevalence of NAFLD is rapidly increasing worldwide, while the pathologyand the underlying mechanism driving NAFLD is not fully understood. In NAFLD, a series of metabolic changes takes place in the liver. However, the alteration of the metabolic pathways in the human liver along the progression of NAFLD,i.e., transition from non-alcoholic steatosis (NAFL) to steatohepatitis (NASH) through cirrhosis remains to be discovered. Here, we sought to examine the metabolic pathways of the human liver across the full histological spectrum of NAFLD.Method: We analyzed the whole liver tissue transcriptomic (RNA-Seq)1 and serum metabolomics data obtained from a large cohort of histologically characterized patients derived from the European NAFLD Registry (n = 206), and developed genome-scale metabolic models (GEMs) of human hepatocytes at different stages of NAFLD. The integrative approach employed in this study has enabled us to understand the regulation of the metabolic pathways of human liver in NAFL, and with progressive NASH-associated fibrosis (F0-F4).Results: Our study 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, by applying genome-scale metabolic modeling, we were able to identify the metabolic differences among carriers of widely validated genetic variants associated with NAFLD/NASH disease severity in three genes (PNPLA3,TM6SF2andHSD17B13).Conclusion: The study provides insights into the underlying pathways of the progressive-fibrosing steatohepatitis. Of note, there is a marked dysregulation of the glycosphingolipid metabolism in the liver of the patients with advanced fibrosis.
|
|
| 13. |
- Sen, Parho, et al.
(författare)
-
Metabolism of human liver on a genome scale in non-alcoholic fatty liver disease
- 2020
-
Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 73:Suppl. 1, s. S671-S672
-
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.
|
|
| 14. |
- Sen, Partho, 1983-, et al.
(författare)
-
Quantitative modeling of human liver reveals dysregulation of glycosphingolipid pathways in nonalcoholic fatty liver disease
- 2022
-
Ingår i: iScience. - : Cell Press. - 2589-0042. ; 25:9
-
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.
|
|
| 15. |
- Wouters, Jasper, et al.
(författare)
-
Comprehensive DNA methylation study identifies novel progression-related and prognostic markers for cutaneous melanoma
- 2017
-
Ingår i: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 15:1, s. 1-16
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Cutaneous melanoma is the deadliest skin cancer, with an increasing incidence and mortality rate. Currently, staging of patients with primary melanoma is performed using histological biomarkers such as tumor thickness and ulceration. As disruption of the epigenomic landscape is recognized as a widespread feature inherent in tumor development and progression, we aimed to identify novel biomarkers providing additional clinical information over current factors using unbiased genome-wide DNA methylation analyses. Methods: We performed a comprehensive DNA methylation analysis during all progression stages of melanoma using Infinium HumanMethylation450 BeadChips on a discovery cohort of benign nevi (n = 14) and malignant melanoma from both primary (n = 33) and metastatic (n = 28) sites, integrating the DNA methylome with gene expression data. We validated the discovered biomarkers in three independent validation cohorts by pyrosequencing and immunohistochemistry. Results: We identified and validated biomarkers for, and pathways involved in, melanoma development (e.g., HOXA9 DNA methylation) and tumor progression (e.g., TBC1D16 DNA methylation). In addition, we determined a prognostic signature with potential clinical applicability and validated PON3 DNA methylation and OVOL1 protein expression as biomarkers with prognostic information independent of tumor thickness and ulceration. Conclusions: Our data underscores the importance of epigenomic regulation in triggering metastatic dissemination through the inactivation of central cancer-related pathways. Inactivation of cell-adhesion and differentiation unleashes dissemination, and subsequent activation of inflammatory and immune system programs impairs anti-tumoral defense pathways. Moreover, we identify several markers of tumor development and progression previously unrelated to melanoma, and determined a prognostic signature with potential clinical utility.
|
|
