The Pattern of Dyslipidemia in Chronic Liver Disease Patients

Farooque, Umar; Lohano, Ashok Kumar; Dahri, Quratulain; Arain, Nazia; Farukhuddin, Fnu; Khadke, Chinmay; Prince, Febin; Farooque, Rizwan; Shehata, Mostafa; Zafar, Muhammad Daim Bin

doi:10.7759/cureus.13259

Cited by 2 publications

(3 citation statements)

References 19 publications

(20 reference statements)

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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 metallothioneins which protect against oxidative stress and are able to chelate heavy metals [ 71 ].…”

Section: Resultssupporting

confidence: 68%

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

et al. 2022

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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.

show abstract

Section: Resultssupporting

confidence: 68%

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

show abstract

“…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: 75%

“…Protein-protein interaction TF-target gene interaction Induced TF Not induced TF Only at the same time Ordered or at the same time suggested that routine monitoring of lipid profiles can improve the outcome for CLD patients [51].…”

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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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.

show abstract

The Pattern of Dyslipidemia in Chronic Liver Disease Patients

Cited by 2 publications

References 19 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)

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