Metallothioneins and Liver Diseases

Oliva, L.; D’Incà, R.; Medici, Valentina; Sturniolo, Giacomo Carlo

doi:10.1142/9789812778949_0014

Cited by 3 publications

(4 citation statements)

References 32 publications

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“…On the pathway level, multiple genesets pointed to a reduced level plasma lipoprotein particle assembly and remodelling which indicates changes in lipid distribution. This aligns with the known dyslipidaemia in chronic liver diseases, including decreasing serum values of LDL, HDL, total cholesterol, and triglycerides with increasing severity of disease, based on which previous studies suggested that routine monitoring of lipid profiles can improve the outcome for CLD patients [70] Furthermore, a down-regulation of response to metal ions was found which could be related to to metallothioneins which protect against oxidative stress and are able to chelate heavy metals [71].…”

Section: Time-concordant Events Reflecting Disease Progressionsupporting

confidence: 69%

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Deriving time-concordant event cascades from gene expression data: A case study for Drug-Induced Liver Injury (DILI)

Liu

Han

Munoz-Muriedas³

et al. 2021

Preprint

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Adverse event pathogenesis is often a complex process which compromises multiple events ranging from the molecular to the phenotypic level. Adverse Outcome Pathways (AOPs) aim to formalize this as temporal sequences of events, in which event relationships should be supported by causal evidence according to the tailored Bradford-Hill criteria. One of the criteria is whether events are consistently observed in a certain temporal order and, in this work, we study this time concordance between gene expression- and histopathology-derived events as data-driven means to generate hypotheses on potentially causal mechanisms. As a case study, we analysed liver data from repeat-dose studies in rats from the TG-GATEs database which comprises measurements across eight timepoints, ranging from 3 hours to 4 weeks post-treatment. We identified time concordant pathway- and transcription factor (TF)- level events preceding adverse histopathology, which serves as surrogate readout for Drug-Induced Liver Injury (DILI). Among known events in DILI, we found some to change strongly before adverse histopathology, e.g. fatty acid beta oxidation, while others were more confident, e.g. bile acid recycling, or frequent, e.g. ATF4-mediated stress response, further characterizing their mechanistic roles. Moreover, we used the temporal order of TF expression and regulon activity to separate induced TFs, such as Cebpa, from post-transcriptionally activated ones, e.g. Srebf2, and subsequently combined this with known functional interactions (TF-target or protein-protein) to derive detailed gene-regulatory mechanisms, such as Hnf4a-dependent Cebpa expression. We additionally evaluate which time concordant events show sustained or increasing activation over time, as this time dependence is favourable for biomarker development, and identify pathways indicating dyslipidaemia, and a decrease in Hnf1a and Hnf4a indicating deteriorating liver function. At the same, time also potentially novel events are identified such as Sox13 which shows a more significant time dependence and -concordance than many known TFs in liver injury. Overall, we demonstrate how time-resolved transcriptomics can derive and support mechanistic hypotheses by quantifying time concordance and how this can be combined with prior causal knowledge, with the aim of both understanding mechanisms of toxicity, as well as potential applications to the AOP framework. We make our results available in the form of a Shiny app (https://github.com/anikaliu/DILICascades_App), which allows users to query events of interest in more detail.

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Section: Time-concordant Events Reflecting Disease Progressionsupporting

confidence: 69%

“…Furthermore, a down-regulation of response to metal ions was found which could be related to metallothioneins which protect against oxidative stress and are able to chelate heavy metals [52].…”

Section: Time-concordant Events Reflecting Disease Progressionmentioning

confidence: 99%

Deriving time-concordant event cascades from gene expression data: A case study for Drug-Induced Liver Injury (DILI)

Liu

Han

Munoz-Muriedas³

et al. 2021

Preprint

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show abstract

“…This aligns with the known dyslipidaemia in chronic liver diseases, including decreasing serum values of LDL, HDL, total cholesterol, and triglycerides with increasing severity of disease, based on which previous studies suggested that routine monitoring of lipid profiles can improve the outcome for CLD patients [ 70 ]. Furthermore, a down-regulation of response to metal ions was found which could be related to metallothioneins which protect against oxidative stress and are able to chelate heavy metals [ 71 ]. Both directions of dysregulation were previously observed in liver diseases: While a negative correlation with disease progression was found in hepatocellular carcinoma [ 72 ], a positive correlation was found in most other liver diseases including acetaminophen-induced liver injury [ 73 ].…”

Section: Resultsmentioning

confidence: 99%

Deriving time-concordant event cascades from gene expression data: A case study for Drug-Induced Liver Injury (DILI)

et al. 2022

View full text Add to dashboard Cite

Adverse event pathogenesis is often a complex process which compromises multiple events ranging from the molecular to the phenotypic level. In toxicology, Adverse Outcome Pathways (AOPs) aim to formalize this as temporal sequences of events, in which event relationships should be supported by causal evidence according to the tailored Bradford-Hill criteria. One of the criteria is whether events are consistently observed in a certain temporal order and, in this work, we study this time concordance using the concept of “first activation” as data-driven means to generate hypotheses on potentially causal mechanisms. As a case study, we analysed liver data from repeat-dose studies in rats from the TG-GATEs database which comprises measurements across eight timepoints, ranging from 3 hours to 4 weeks post-treatment. We identified time concordant gene expression-derived events preceding adverse histopathology, which serves as surrogate readout for Drug-Induced Liver Injury (DILI). We find known mechanisms in DILI to be time-concordant, and show further that significance, frequency and log fold change (logFC) of differential expression are metrics which can additionally prioritize events although not necessary to be mechanistically relevant. Moreover, we used the temporal order of transcription factor (TF) expression and regulon activity to identify transcriptionally regulated TFs and subsequently combined this with prior knowledge on functional interactions to derive detailed gene-regulatory mechanisms, such as reduced Hnf4a activity leading to decreased expression and activity of Cebpa. At the same time, also potentially novel events are identified such as Sox13 which is highly significantly time-concordant and shows sustained activation over time. Overall, we demonstrate how time-resolved transcriptomics can derive and support mechanistic hypotheses by quantifying time concordance and how this can be combined with prior causal knowledge, with the aim of both understanding mechanisms of toxicity, as well as potential applications to the AOP framework. We make our results available in the form of a Shiny app (https://anikaliu.shinyapps.io/dili_cascades), which allows users to query events of interest in more detail.

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“…In MT1, there existed MT1A, MT1B, MT1E, MT1F, MT1G, MT1H, MT1M, and MT1X isoforms ( 49 ). These proteins mainly regulated copper and zinc homeostasis in the liver and protected hepatocytes from oxidative damage ( 50 ). Thus, MT1 expression negatively correlated with the damage status of chronic liver diseases ( 51 ).…”

Section: Discussionmentioning

confidence: 99%

Integrated Analysis of Key Genes and Pathways Involved in Nonalcoholic Steatohepatitis Improvement After Roux-en-Y Gastric Bypass Surgery

Zhou

et al. 2021

Front. Endocrinol.

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BackgroundAs the incidence of nonalcoholic fatty liver disease (NAFLD) increases globally, nonalcoholic steatohepatitis (NASH) has become the second common cause of liver transplantation for liver diseases. Recent evidence shows that Roux-en-Y gastric bypass (RYGB) surgery obviously alleviates NASH. However, the mechanism underlying RYGB induced NASH improvement is still elusive.MethodsWe obtained datasets, including hepatic gene expression data and histologic NASH status, at baseline and 1 year after RYGB surgery. Differentially expressed genes (DEGs) were identified comparing gene expression before and after RYGB surgery in each dataset. Common DEGs were obtained between both datasets and further subjected to functional and pathway enrichment analysis. Protein–protein interaction (PPI) network was constructed, and key modules and hub genes were also identified.ResultsIn the present study, GSE106737 and GSE83452 datasets were included. One hundred thirty common DEGs (29 up-regulated and 101 down-regulated) were identified between GSE106737 and GSE83452 datasets. KEGG analysis showed that mineral absorption, IL-17 signaling pathway, osteoclast differentiation, and TNF signaling pathway were significantly enriched. Based on the PPI network, IGF1, JUN, FOS, LDLR, TYROBP, DUSP1, CXCR4, ATF3, CXCL2, EGR1, SAA1, CTSS, and PPARA were identified as hub genes, and three functional modules were also extracted.ConclusionThis study identifies the global gene expression change in the liver of NASH patients before and after RYGB surgery in a bioinformatic method. Our findings will contribute to the understanding of molecular biological changes underlying NASH improvement after RYGB surgery.

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Metallothioneins and Liver Diseases

Cited by 3 publications

References 32 publications

Deriving time-concordant event cascades from gene expression data: A case study for Drug-Induced Liver Injury (DILI)

Deriving time-concordant event cascades from gene expression data: A case study for Drug-Induced Liver Injury (DILI)

Deriving time-concordant event cascades from gene expression data: A case study for Drug-Induced Liver Injury (DILI)

Integrated Analysis of Key Genes and Pathways Involved in Nonalcoholic Steatohepatitis Improvement After Roux-en-Y Gastric Bypass Surgery

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