Download files
Abstract
Overweight and obesity are major risk factors for development of non-alcoholic fatty liver disease (NAFLD) and non-response to antiviral therapy in chronic hepatitis C (HCV). The overall aim of this thesis was to elucidate key inflammatory and metabolic genes associated with liver injury and non-response to antiviral therapy in obesity. To achieve this, key inflammatory factors were studied in three compartments: the peripheral blood, adipose tissue and the liver.
With respect to the peripheral blood, increased expression of SOCS3 in obese non-responders to antiviral therapy for chronic HCV was found. Increased SOCS3 expression was associated with reduced anti-HCV effector cytokine production and enhanced IL-6 production. Ex vivo experiments confirmed that IL-6 induced SOCS3 in peropheral blood mononuclear cells. These data indicate an association between the SOCS3/IL-6 axis and an impaired anti-HCV cytokine response in obese non-responders to antiviral therapy.
A novel transcriptomics platform, Whole Genome-cDNA-mediated Annealing, Selection, Extension, and Ligation (WG-DASL), was used to identify differentially expressed inflammatory and metabolic genes in the adipose and liver tissues from obese subjects with or without NAFLD. Genes in the ceramide/sphingolipid pathway were found to be dysregulated in adipose and liver tissues, potentially impacting the extent of liver disease. In this regard, genes promoting ceramide formation were increased whilst those promoting their degradation were decreased, particularly in the liver. This gene profile correlated with markers of liver injury and inflammatory cytokine expression.
Finally, the role of microRNA as regulators of inflammatory and metabolic genes mediating liver injury was studied in liver samples from patients with NAFLD using microarray. Upregulation of miR-135a-3p was found in patients with normal liver histology versus NAFLD. This correlated inversely with hepatic expression of SCD-1, a key lipogenic gene, with a trend towards a negative correlation with the proinflammatory genes, IL-6 and IL-1. These findings suggest that the increased expression of miR-135a-3p may induce a protective effect against the development of NAFLD.
The accumulated data indicate that in obesity, inflammatory and lipid mediators are associated with liver disease in NAFLD and may impact on the response to antiviral therapy in chronic HCV. While these data require further validation, these studies have improved our understanding of the link between obesity and inflammation in blood, adipose tissue and the liver in relation to chronic liver disease