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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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- Attaye, Ilias, et al.
(författare)
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Protein supplementation changes gut microbial diversity and derived metabolites in subjects with type 2 diabetes
- 2023
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Ingår i: ISCIENCE. - 2589-0042. ; 26:8
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Tidskriftsartikel (refereegranskat)abstract
- High-protein diets are promoted for individuals with type 2 diabetes (T2D). How-ever, effects of dietary protein interventions on (gut-derived) metabolites in T2D remains understudied. We therefore performed a multi-center, randomized -controlled, isocaloric protein intervention with 151 participants following either 12-week high-protein (HP; 30Energy %, N = 78) vs. low-protein (LP; 10 Energy%, N = 73) diet. Primary objectives were dietary effects on glycemic control which were determined via glycemic excursions, continuous glucose monitors and HbA1c. Secondary objectives were impact of diet on gut microbiota composition and-derived metabolites which were determined by shotgun-metagenomics and mass spectrometry. Analyses were performed using delta changes adjusting for center, baseline, and kidney function when appropriate. This study found that a short-term 12-week isocaloric protein modulation does not affect glycemic parameters or weight in metformin-treated T2D. However, the HP diet slightly worsened kidney function, increased alpha-diversity, and production of potentially harmful microbiota-dependent metabolites, which may affect host metabolism upon prolonged exposure.
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- Brial, François, et al.
(författare)
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Human and preclinical studies of the host-gut microbiome co-metabolite hippurate as a marker and mediator of metabolic health
- 2021
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Ingår i: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 70:11, s. 2105-2114
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Gut microbial products are involved in regulation of host metabolism. In human and experimental studies, we explored the potential role of hippurate, a hepatic phase 2 conjugation product of microbial benzoate, as a marker and mediator of metabolic health.DESIGN: In 271 middle-aged non-diabetic Danish individuals, who were stratified on habitual dietary intake, we applied 1H-nuclear magnetic resonance (NMR) spectroscopy of urine samples and shotgun-sequencing-based metagenomics of the gut microbiome to explore links between the urine level of hippurate, measures of the gut microbiome, dietary fat and markers of metabolic health. In mechanistic experiments with chronic subcutaneous infusion of hippurate to high-fat-diet-fed obese mice, we tested for causality between hippurate and metabolic phenotypes.RESULTS: In the human study, we showed that urine hippurate positively associates with microbial gene richness and functional modules for microbial benzoate biosynthetic pathways, one of which is less prevalent in the Bacteroides 2 enterotype compared with Ruminococcaceae or Prevotella enterotypes. Through dietary stratification, we identify a subset of study participants consuming a diet rich in saturated fat in which urine hippurate concentration, independently of gene richness, accounts for links with metabolic health. In the high-fat-fed mice experiments, we demonstrate causality through chronic infusion of hippurate (20 nmol/day) resulting in improved glucose tolerance and enhanced insulin secretion.CONCLUSION: Our human and experimental studies show that a high urine hippurate concentration is a general marker of metabolic health, and in the context of obesity induced by high-fat diets, hippurate contributes to metabolic improvements, highlighting its potential as a mediator of metabolic health.
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- Burraco, Pablo, et al.
(författare)
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Lack of impact of radiation on blood physiology biomarkers of Chernobyl tree frogs
- 2021
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Ingår i: Frontiers in Zoology. - : Frontiers Media S.A.. - 1742-9994. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Human actions have altered natural ecosystems worldwide. Among the many pollutants released to the environment, ionizing radiation can cause severe damage at different molecular and functional levels. The accident in the Chernobyl Nuclear Power Plant (1986) caused the largest release of ionizing radiation to the environment in human history. Here, we examined the impact of the current exposure to ionizing radiation on blood physiology biomarkers of adult males of the Eastern tree frog (Hyla orientalis) inhabiting within and outside the Chernobyl Exclusion Zone. We measured the levels of eight blood parameters (sodium, potassium, chloride, ionized calcium, total carbon dioxide, glucose, urea nitrogen, and anion gap), physiological markers of homeostasis, as well as of liver and kidney function.Results: Levels of blood physiology biomarkers did not vary in function of the current exposure of tree frogs to ionizing radiation within the Chernobyl Exclusion Zone. Physiological blood levels were similar in frogs inhabiting Chernobyl (both in areas with medium-high or low radiation) than in tree frogs living outside Chernobyl exposed only to background radiation levels.Conclusions: The observed lack of effects of current radiation levels on blood biomarkers can be a consequence of the low levels of radiation currently experienced by Chernobyl tree frogs, but also to the fact that our sampling was restricted to active breeding males, i.e. potentially healthy adult individuals. Despite the clear absence of effects of current radiation levels on physiological blood parameters in tree frogs, more research covering different life stages and ecological scenarios is still needed to clarify the impact of ionizing radiation on the physiology, ecology, and dynamics of wildlife inhabiting radioactive-contaminated areas.
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- Car, Clement, et al.
(författare)
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Unusual evolution of tree frog populations in the Chernobyl exclusion zone
- 2022
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Ingår i: Evolutionary Applications. - : John Wiley & Sons. - 1752-4571. ; 15:2, s. 203-219
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Tidskriftsartikel (refereegranskat)abstract
- Despite the ubiquity of pollutants in the environment, their long-term ecological consequences are not always clear and still poorly studied. This is the case concerning the radioactive contamination of the environment following the major nuclear accident at the Chernobyl nuclear power plant. Notwithstanding the implications of evolutionary processes on the population status, few studies concern the evolution of organisms chronically exposed to ionizing radiation in the Chernobyl exclusion zone. Here, we examined genetic markers for 19 populations of Eastern tree frog (Hyla orientalis) sampled in the Chernobyl region about thirty years after the nuclear power plant accident to investigate microevolutionary processes ongoing in local populations. Genetic diversity estimated from nuclear and mitochondrial markers showed an absence of genetic erosion and higher mitochondrial diversity in tree frogs from the Chernobyl exclusion zone compared to other European populations. Moreover, the study of haplotype network permitted us to decipher the presence of an independent recent evolutionary history of Chernobyl exclusion zone's Eastern tree frogs caused by an elevated mutation rate compared to other European populations. By fitting to our data a model of haplotype network evolution, we suspected that Eastern tree frog populations in the Chernobyl exclusion zone have a high mitochondrial mutation rate and small effective population sizes. These data suggest that Eastern tree frog populations might offset the impact of deleterious mutations because of their large clutch size, but also question the long-term impact of ionizing radiation on the status of other species living in the Chernobyl exclusion zone.
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- Chatre, Clément, et al.
(författare)
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Influence of Surface-Active Substances and Substrates on the Wettability of Individual Aerosol Particles during Condensation by Environmental Scanning Electron Microscopy
- 2023
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Ingår i: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 39:8, s. 2957-2965
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Tidskriftsartikel (refereegranskat)abstract
- The formation of liquid cloud droplets from aerosol particles in the Earth atmosphere is still under debate particularly because of the difficulties to quantify the importance of bulk and surface effects in these processes. Recently, single-particle techniques have been developed to access experimental key parameters at the scale of individual particles. Environmental scanning electron microscopy (ESEM) has the advantage to provide in situ monitoring of the water uptake of individual microscopic particles deposited on solid substrates. In this work, ESEM was used to compare droplet growth on pure ammonium sulfate (NH4)2SO4 and mixed sodium dodecyl sulfate/ammonium sulfate (SDS/(NH4)2SO4) particles and to explore the role of experimental parameters, such as the hydrophobic–hydrophilic character of the substrate, on this growth. With hydrophilic substrates, the growth on pure salt particles was strongly anisotropic, but this anisotropy was suppressed by the presence of SDS. With hydrophobic substrates, it is the wetting behavior of the liquid droplet that is impacted by the presence of SDS. The wetting behavior of the pure (NH4)2SO4 solution on a hydrophobic surface shows a step-by-step mechanism that can be attributed to successive pinning–depinning phenomena at the triple-phase line frontier. Unlike the pure (NH4)2SO4 solution, the mixed SDS/(NH4)2SO4 solution did not show such a mechanism. Therefore, the hydrophobic–hydrophilic character of the substrate plays an important role in the stability and dynamics of the liquid droplets’ nucleation by water vapor condensation. In particular, hydrophilic substrates are not suited for the investigation of the hygroscopic properties (deliquescence relative humidity (DRH) and hygroscopic growth factor (GF)) of particles. Using hydrophobic substrates, data show that the DRH of (NH4)2SO4 particles is measured within 3% accuracy on the RH and their GF could indicate a size-dependent effect in the micrometer range. The presence of SDS does not seem to modify the DRH and GF of (NH4)2SO4 particles. This study shows that the water uptake on deposited particles is a complex process but, once carefully taken into account, ESEM is a suitable technique to study them.
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- 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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| 10. |
- 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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