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Title: | A Quantitative Systems Pharmacology Platform Reveals NAFLD Pathophysiological States and Targeting Strategies |
Author: | Lefever, DE Miedel, MT Pei, F DiStefano, JK Debiasio, R Shun, TY Saydmohammed, M Chikina, M Vernetti, LA Soto-Gutierrez, A Monga, SP Bataller, R Behari, J Yechoor, VK Bahar, I Gough, A Stern, AM Taylor, DL |
Keywords: | CMap CONNECTIVITY MAP Drug combinations drug discovery drug repurposing fibrosis liver lobular inflammation MAFLD metabolic-associated fatty liver disease microphysiology systems MPS NAFLD NASH network proximity non-alcoholic fatty liver disease non-alcoholic steatohepatitis QSP quantitative systems pharmacology Steatosis Article Bioinformatics Biological Marker cell nucleus receptor CMap CONNECTIVITY MAP Connectome Discovery Disease Exacerbation Drug Combinations Drug Development Drug Discovery Drug Repositioning Drug Repurposing Fatty Liver-Disease Fibrosis Gene Expression Gene Mapping Gene Sequence gene set variation analysis Gene-Expression Genetic Transcription HEPATIC-FIBROSIS Homeostasis Human Inflammation KEGG Lipid Metabolism Liver Liver Biopsy Liver Cirrhosis lobular inflammation Machine Learning MAFLD metabolic fatty liver Metabolic-associated fatty liver disease microphysiology systems MPs Nafld Nash network proximity Non Insulin Dependent Diabetes Mellitus Non-alcoholic fatty |
Abstract: | Non-alcoholic fatty liver disease (NAFLD) has a high global prevalence with a heterogeneous and complex pathophysiology that presents barriers to traditional targeted therapeutic approaches. We describe an integrated quantitative systems pharmacology (QSP) platform that comprehensively and unbiasedly defines disease states, in contrast to just individual genes or pathways, that promote NAFLD progression. The QSP platform can be used to predict drugs that normalize these disease states and experimentally test predictions in a human liver acinus microphysiology system (LAMPS) that recapitulates key aspects of NAFLD. Analysis of a 182 patient-derived hepatic RNA-sequencing dataset generated 12 gene signatures mirroring these states. Screening against the LINCS L1000 database led to the identification of drugs predicted to revert these signatures and corresponding disease states. A proof-of-concept study in LAMPS demonstrated mitigation of steatosis, inflammation, and fibrosis, especially with drug combinations. Mechanistically, several structurally diverse drugs were predicted to interact with a subnetwork of nuclear receptors, including pregnane X receptor (PXR; NR1I2), that has evolved to respond to both xenobiotic and endogenous ligands and is intrinsic to NAFLD-associated transcription dysregulation. In conjunction with iPSC-derived cells, this platform has the potential for developing personalized NAFLD therapeutic strategies, informing disease mechanisms, and defining optimal cohorts of patients for clinical trials. |
Note: | Reproducció del document publicat a: https://doi.org/10.3390/metabo12060528 |
It is part of: | Metabolites, 2022, 12, 6-NA |
URI: | http://hdl.handle.net/2445/209165 |
Related resource: | https://doi.org/10.3390/metabo12060528 |
ISSN: | Lefever, DE;Miedel, MT;Pei, F;DiStefano, JK;Debiasio, R;Shun, TY;Saydmohammed, M;Chikina, M;Vernetti, LA;Soto-Gutierrez, A;Monga, SP;Bataller, R;Behari, J;Yechoor, VK;Bahar, I;Gough, A;Stern, AM;Taylor, DL. A Quantitative Systems Pharmacology Platform RevealsFLD Pathophysiological States and Targeting Strategies. Metabolites, 2022, 12, 6-NA |
Appears in Collections: | Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) |
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A Quantitative Systems Pharmacology Platform Reveals NAFLD Pathophysiological States and Targeting Strategies_Metabolites.pdf | 7.54 MB | Adobe PDF | View/Open |
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