Abstract
BackgroundCardiovascular disease (CVD) remains the major cause of excess mortality in patients with non-alcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the individual contribution of NAFLD to CVD risk factors in the absence of pathogenic influences from other comorbidities often found in NAFLD patients, by using an established in-vitro model of hepatic steatosis.MethodsHistopathological events in non-alcoholic fatty liver disease were recapitulated by focused metabolic nutrient overload of hepatoblastoma C3A cells, using oleate-treated-cells and untreated controls for comparison. Microarray and proteomic data from cell culture experiments were integrated into a custom-built systems biology database and proteogenomics analysis performed. Candidate genes with significant dysregulation and concomitant changes in protein abundance were identified and STRING association and enrichment analysis performed to identify putative pathogenic pathways.ResultsThe search strategy yielded 3 candidate genes that were specifically and significantly up-regulated in nutrient-overloaded cells compared to untreated controls: fibrinogen alpha chain (2.2 fold), fibrinogen beta chain (2.3 fold) and fibrinogen gamma chain (2.1 fold) (all rank products pfp <0.05). Fibrinogen alpha and gamma chain also demonstrated significant concomitant increases in protein abundance (3.8-fold and 2.0-fold, respectively, p <0.05).ConclusionsIn-vitro modelling of NAFLD and reactive oxygen species formation in nutrient overloaded C3A cells, in the absence of pathogenic influences from other comorbidities, suggests that NAFLD is an isolated determinant of CVD. Nutrient overload-induced up-regulation of all three fibrinogen component subunits of the coagulation cascade provides a possible mechanism to explain the excess CVD mortality observed in NAFLD patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12944-015-0069-3) contains supplementary material, which is available to authorized users.
Highlights
Cardiovascular disease (CVD) remains the major cause of excess mortality in patients with nonalcoholic fatty liver disease (NAFLD)
This may explain the differences in demographic data observed in Asia compared to elsewhere in the world, including a younger age distribution and a higher proportion of patients who are judged lean by Body Mass Index, but show an altered metabolic profile associated with obesity [4, 5]
We developed an in vitro model of cellular steatosis by exposing hepatoblastoma C3A cells to nutrient overload, which reproduces the characteristic pathophysiological changes found in NAFLD, including intracellular triglyceride accumulation and reactive oxygen species (ROS) formation [16]
Summary
Cardiovascular disease (CVD) remains the major cause of excess mortality in patients with nonalcoholic fatty liver disease (NAFLD). The term “Metabolic Syndrome” (MetS) describes a clinical cluster of diseases that tend to aggregate in individuals over time, including central obesity, hypertension, impaired fasting glucose and dyslipidemia [9,10,11]. Together these components create a pro-atherogenic environment that is postulated to accelerate atherosclerosis and increase the risk of cardiovascular diseases. To date, there are no experimental genomic or proteomic studies that examine whether NAFLD is an isolated risk factor for CVD in absence of other components of MetS, or if these conditions have a common cause
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