Review article: shared disease mechanisms between non‐alcoholic fatty liver disease and metabolic syndrome – translating knowledge from systems biology to the bedside

Abstract

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 genedrug 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.

Changing trajectories of serum uric acid and risk of non-alcoholic fatty liver disease: a prospective cohort study

“…An FPG level ≥ 7.0 mmol/L or the use of glucose-lowering drugs was considered as diabetes. According to the harmonized definition of the metabolic syndrome (MS) established in 2009, the MS was identified by requiring the existence of least three or more criteria [16]: (1) abdominal obesity referred to WC ≥ 90 cm in men, WC ≥ 80 cm in women; (2) high TG ≥ 1.7 mmol/L or the use of drug treatment for elevated TG; (3) low HDL-C < 1.0 mmol/L in men, HDL-C < 1.3 mmol/L in women or the use of drug treatment for reduced HDL-C; (4) elevated blood pressure of systolic ≥ 130 mmHg and/ or diastolic ≥ 85 mmHg, or the use of an antihypertensive drug treatment; and (5) high FPG ≥ 5.6 mmol/L.…”

“…Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder of the liver and may predispose the affected individual to the development of cirrhosis and hepatocellular carcinoma [1]. Lifestyle changes in developed Western and Asian countries have led to an increase in the incidence of NAFLD.…”

Methodological Tools for Exploring Novel Biopharmaceutical Approaches to the Metabolic Syndrome and Related Disorders

“…A strict metabolic control may alter the natural course of the MetS [22]. This notion, together with the epidemiological data summarized above, fully justifies a major research effort to develop and evaluate innovative pharmacological treatment options of the individual constitutive features of the MetS [2,23,24]. Some of these features may also benefit from metabolic surgery [25][26][27][28].…”

Rooibos (Aspalathus linearis) and Honeybush (Cyclopiaspp.): From Bush Teas to Potential Therapy for Cardiovascular Disease

“…Insulin resistance, a key finding in the metabolic syndrome, is characterised by alterations in glucose uptake in insulin sensitive tissues such as the liver, skeletal muscle and adipose tissue [134]. Non-alcoholic fatty liver disease (NAFLD), characterised by fat accumulation in the liver, is an independent predictor of the metabolic syndrome which influences the progression of cardiovascular disease [135]. Since NAFLD is complex, utilising therapeutic strategies with multiple targets may be beneficial.…”