The large number of patients with NASH-related end-stage liver disease, and the emerging pharmacological treatment options, means that there is an urgent need for valid and reproducible biomarkers of disease development and progression. The transsulfuration pathway (TSP) is coupled to the production of the antioxidant glutathione (GSH) and the signal molecule hydrogen sulfide (H 2S), and both have been linked to the pathogenesis of NAFLD. Dietary overload is believed to be the main underlying driver, but the molecular mechanisms behind the lipotoxicity remain unclear. The primary characteristic of NAFLD is the hepatic accumulation of lipids, mainly triacylglycerols (TAGs), due to the increased influx of free fatty acids (FFA). NASH can lead to fibrosis and eventually to cirrhosis, liver failure, and hepatocellular carcinoma. NAFLD is a disease continuum that ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), which is characterized by inflammation and hepatocyte damage. The rapid increase in prevalence during recent years parallels the increasing occurrence of obesity and the metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is present in 25% of the population worldwide. Further investigation of the TSP in relation to NAFLD may reveal mechanisms involved in the development and progression of NAFLD. However, dysfunctions in the TSP and related pathways, in terms of enzyme expression and the plasma levels of the metabolites (e.g., homocysteine, cystathionine, and cysteine), have been reported in NAFLD and liver cirrhosis in both animal models and humans. A causative link between the TSP and NAFLD has not been established. The key enzymes of the TSP, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), are highly expressed in the liver and deficient CBS and CSE expression causes hepatic steatosis, inflammation, and fibrosis in animal models. Homocysteine will also be increased due to impairment of the folate and methionine cycles. Impaired activity of the TSP will cause an increase in homocysteine and a decrease in cysteine levels. The TSP is closely linked to other pathways such as the folate and methionine cycles, hydrogen sulfide (H 2S) and glutathione (GSH) production. Precise control of this pathway is critical for maintenance of optimal cellular function. The transsulfuration pathway (TSP) is a metabolic pathway regulating homocysteine and cysteine metabolism and is vital in controlling sulfur balance in the organism. NAFLD is associated with obesity and metabolic syndrome, but its pathophysiology is complex and only partly understood. The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and approximately 25% of the global population may have NAFLD.
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