ArticleNPJ systems biology and applications2018
Multi-scale, whole-system models of liver metabolic adaptation to fat and sugar in non-alcoholic fatty liver disease.
Article in NPJ systems biology and applications, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 1 of them a synthesis that pooled it.
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Who cites it
22 citing papers in PubMed, 1 synthesis or guideline pooled it, 38 citations in OpenAlex.
- Application of Magnetic Resonance Imaging in Liver Biomechanics: A Systematic Review.Frontiers in physiology · 2021Pooled it
- Diagnostic performance of ultrasound-derived fat fraction for detecting hepatic steatosis in patients with tumor-related liver disease.Abdominal radiology (New York) · 2026Article
- Quantitative systems toxicology approach that integrates PBPK and core hepatic metabolism: a case study with valproic acid.Frontiers in pharmacology · 2026Article
- Distinct network patterns emerge from Cartesian and XOR epistasis models: a comparative network science analysis.BioData mining · 2024Article
- Distinct Network Patterns Emerge from Cartesian and XOR Epistasis Models: A Comparative Network Science Analysis.Research square · 2024Article
- A short-term high-sugar diet is an aggravating factor in experimental allergic contact dermatitis.Heliyon · 2023Article
- Multi-Modality, Multi-Dimensional Characterization of Pediatric Non-Alcoholic Fatty Liver Disease.Metabolites · 2023Article
- Proteomic analysis reveals USP7 as a novel regulator of palmitic acid-induced hepatocellular carcinoma cell death.Cell death & disease · 2022Article
- Article
- Dietary carbohydrates and fats in nonalcoholic fatty liver disease.Nature reviews. Gastroenterology & hepatology · 2021Review
- Importance of the biomass formulation for cancer metabolic modeling and drug prediction.iScience · 2021Article
- Addressing the heterogeneity in liver diseases using biological networks.Briefings in bioinformatics · 2021Review
- Article
- Virtual metabolic human dynamic model for pathological analysis and therapy design for diabetes.iScience · 2021Article
- Emergent Properties of the HNF4α-PPARγ Network May Drive Consequent Phenotypic Plasticity in NAFLD.Journal of clinical medicine · 2020Article
- Computational Modeling of Fructose Metabolism and Development in NAFLD.Frontiers in bioengineering and biotechnology · 2020Article
- Network Modeling Approaches and Applications to Unravelling Non-Alcoholic Fatty Liver Disease.Genes · 2019Review
- Biomarkers and subtypes of deranged lipid metabolism in non-alcoholic fatty liver disease.World journal of gastroenterology · 2019Review
- Model-inferred mechanisms of liver function from magnetic resonance imaging data: Validation and variation across a clinically relevant cohort.PLoS computational biology · 2019Article
- Investigating the deregulation of metabolic tasks via Minimum Network Enrichment Analysis (MiNEA) as applied to nonalcoholic fatty liver disease using mouse and human omics data.PLoS computational biology · 2019Article
Corrections and comments
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Authors and funding
8 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a serious public health issue associated with high fat, high sugar diets. However, the molecular mechanisms mediating NAFLD pathogenesis are only partially understood. Here we adopt an iterative multi-scale, systems biology approach coupled to in vitro experimentation to investigate the roles of sugar and fat metabolism in NAFLD pathogenesis. The use of fructose as a sweetening agent is controversial; to explore this, we developed a predictive model of human monosaccharide transport, signalling and metabolism. The resulting quantitative model comprising a kinetic model describing monosaccharide transport and insulin signalling integrated with a hepatocyte-specific genome-scale metabolic network (GSMN). Differential kinetics for the utilisation of glucose and fructose were predicted, but the resultant triacylglycerol production was predicted to be similar for monosaccharides; these predictions were verified by in vitro data. The role of physiological adaptation to lipid overload was explored through the comprehensive reconstruction of the peroxisome proliferator activated receptor alpha (PPARα) regulome integrated with a hepatocyte-specific GSMN. The resulting qualitative model reproduced metabolic responses to increased fatty acid levels and mimicked lipid loading in vitro. The model predicted that activation of PPARα by lipids produces a biphasic response, which initially exacerbates steatosis. Our data support the evidence that it is the quantity of sugar rather than the type that is critical in driving the steatotic response. Furthermore, we predict PPARα-mediated adaptations to hepatic lipid overload, shedding light on potential challenges for the use of PPARα agonists to treat NAFLD.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.