Review Article

Shared Disease Mechanisms Between Nonalcoholic Fatty Liver Disease and Metabolic Syndrome

Translating Knowledge From Systems Biology to the Bedside

Silvia Sookoian; Carlos J. Pirola


Aliment Pharmacol Ther. 2019;49(5):516-527. 

In This Article

Abstract and Introduction


Background Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide. Characterised by abnormal fat accumulation in the liver, NAFLD presents high degree of comorbidity with disorders of the metabolic syndrome, including type 2 diabetes, obesity and cardiovascular disease. These comorbidities have strong negative impact on the natural course of NAFLD and vice versa, whereby the presence of NAFLD substantially modifies the course and prognosis of metabolic syndrome-associated diseases.

Aim To use systems biology strategies to interrogate disease mechanisms that are common to NAFLD and metabolic syndrome.

Methods We mapped shared gene/protein-disease interaction networks, we performed gene-disease enrichment analysis to assess pleiotropy, and we created a gene-drug connectivity network.

Results We found that a shared network of genes/proteins is overrepresented by immune response-related pathways, post-translational modifications of nuclear receptors, and platelet-related processes, including activation and platelet signalling. Likewise, gene-based disease-enrichment analysis suggested underlying molecular effectors that are shared with major systemic disorders, including diverse autoimmune diseases, kidney, respiratory and nervous system disorders, cancer and infectious diseases. The shared list of genes/proteins was enriched in drug targets for anti-inflammatory therapy, drugs used to treat cardiovascular diseases, antimicrobial agents and phytochemicals, among many other approved pharmaceutical compounds. By leveraging on publicly available OMICs data, we were able to show that shared loci are not necessarily affected by reverse causality.

Conclusion We provide evidence indicating that NAFLD treatment, including severe histological traits, cannot be limited to the use of a single drug, as it rather requires a multi-target therapeutic approach.


Non-alcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic liver disease worldwide.[1,2,3] Non-alcoholic steatohepatitis (NASH) and NASH-fibrosis, the severe and progressive clinical forms of NAFLD, impose clinical challenges because they are difficult to detect in the earlier stages and their presence may predispose the affected individual to the development of cirrhosis and hepatocellular carcinoma.[1,2,3]

In addition, NAFLD presents high degree of concomitance with the Metabolic syndrome-associated disorders, including type 2 diabetes, obesity, cardiovascular disease and dyslipidemia. These comorbidities exert a strong negative impact on the natural course of NAFLD.[1,2,3] In fact, NAFLD severity is highly influenced by the presence of type 2 diabetes and obesity, both of which increase the likelihood of worsening liver fibrosis and development of end-stage liver disease.[1,2,3,4] Likewise, presence of NAFLD significantly influences not only the development of insulin resistance[5,6,7] but also the course of cardiovascular disease.[8,9,10,11,12]

Considered jointly, the aforementioned evidence suggests the existence of shared pathogenic mechanisms between NAFLD and Metabolic syndrome-associated diseases.[13] Hence, this imparts the challenge of designing and implementing treatment strategies for simultaneously targeting multiple phenotypes. It thus becomes essential not only to uncover the shared pathogenic networks that link NAFLD, NASH, and Metabolic syndrome but also to understand how they interact with each other to define combined preventive strategies and to explore novel therapeutic approaches.

Here, we hypothesise that NAFLD and the Metabolic syndrome phenotypes present common etiology and share similar underlying biological processes. In addition, factors involved in the progression of NAFLD, such as inflammation and fibrogenesis, represent common pathophenotypes implicated in the progression of complex systemic diseases. To test these hypotheses, we adopted systems biology strategies, which rely on the assumption that systemic disorders originate from the disruption of common regulatory gene networks that govern cellular and tissue physiology. This assumption is of particular relevance for explaining the presence of comorbidities associated with NAFLD. Therefore, our aim was to map gene/protein-disease interaction networks, which would conceptually allow the identification of molecular mediators that link related disorders/diseases.

Our approach first involved search of the pertinent biomedical literature related to genes and/or proteins associated with diseases of interest (NAFLD and NAFLD-severity associated phenotypes, including inflammation and fibrosis, type 2 diabetes, obesity, arterial hypertension and dyslipidemia) which was subjected to literature-enrichment analysis. This step provided us with a theoretical framework for testing the hypothesis of common disease pathogenic mechanisms between NAFLD and Metabolic syndrome. We next selected genes that are shared among all the phenotypes mentioned above, which were used to predict the presence of comorbidity with systemic diseases, as well as to explore potential genes-drugs relationships to create a gene-drug interaction network that allows predicting potential therapeutic targets.