Dataset Information

Multi-scale, whole-system models of liver metabolic adaptation to fat and sugar in non-alcoholic fatty liver disease.

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 (PPAR?) 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 PPAR? 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 PPAR?-mediated adaptations to hepatic lipid overload, shedding light on potential challenges for the use of PPAR? agonists to treat NAFLD.

SUBMITTER: Maldonado EM

PROVIDER: S-EPMC6102210 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Multi-scale, whole-system models of liver metabolic adaptation to fat and sugar in non-alcoholic fatty liver disease.

Maldonado Elaina M EM Fisher Ciarán P CP Mazzatti Dawn J DJ Barber Amy L AL Tindall Marcus J MJ Plant Nicholas J NJ Kierzek Andrzej M AM Moore J Bernadette JB

NPJ systems biology and applications 20180820

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 o ...[more]

PMID: 30131870

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Project description:BackgroundSweetened beverage intake may play a role in non-alcoholic fatty liver disease (NAFLD) development, but scientific evidence on their role is limited. This study examined associations between sugar-sweetened beverages (SSB), low/no-calorie beverages (LNCB) and fruit juice (FJ) intakes and NAFLD in four European studies.MethodsData for 42,024 participants of Lifelines Cohort, NQPlus, PREDIMED-Plus and Alpha Omega Cohort were cross-sectionally analysed. NAFLD was assessed using Fatty Liver Index (FLI) (≥60). Restricted cubic spline analyses were used to visualize dose-response associations in Lifelines Cohort. Cox proportional hazard regression analyses with robust variance were performed for associations in individual cohorts; data were pooled using random effects meta-analysis. Models were adjusted for demographic, lifestyle, and other dietary factors.ResultsEach additional serving of SSB per day was associated with a 7% higher FLI-defined NAFLD prevalence (95%CI 1.03-1.11). For LNCB, restricted cubic spline analysis showed a nonlinear association with FLI-defined NAFLD, with the association getting stronger when consuming ≤1 serving/day and levelling off at higher intake levels. Pooled Cox analysis showed that intake of >2 LNCB servings/week was positively associated with FLI-defined NAFLD (PR 1.38, 95% CI 1.15-1.61; reference: non-consumers). An inverse association was observed for FJ intake of ≤2 servings/week (PR 0.92, 95% CI: 0.88-0.97; reference: non-consumers), but not at higher intake levels. Theoretical replacement of SSB with FJ showed no significant association with FLI-defined NAFLD prevalence (PR 0.97, 95% CI 0.95-1.00), whereas an adverse association was observed when SSB was replaced with LNCB (PR 1.12, 95% CI 1.03-1.21).ConclusionsPooling results of this study showed that SSB and LNCB were positively associated with FLI-defined NAFLD prevalence. Theoretical replacement of SSB with LNCB was associated with higher FLI-defined NAFLD prevalence. An inverse association was observed between moderate intake of FJ and FLI-defined NAFLD. Our results should be interpreted with caution as reverse causality cannot be ruled out.

Dataset Information

Multi-scale, whole-system models of liver metabolic adaptation to fat and sugar in non-alcoholic fatty liver disease.

Publications

Multi-scale, whole-system models of liver metabolic adaptation to fat and sugar in non-alcoholic fatty liver disease.

Similar Datasets

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