Chronic liver disease (CLD) is the replacement of liver tissue by scar as a consequence of persistent hepatic injury. The main causes of liver injury include alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD) and viral hepatitis. CLD is a progressive life threatening condition and responsible for 170,000 deaths per annum in Europe. NAFLD is characterized by an accumulation of hepatic fat (triglycerides); it is considered as the hepatic manifestation of the metabolic syndrome which comprises insulin resistance, obesity, and hyperlipidemia. The substantial increase of NAFLD incidence tracks obesity epidemic as a result of unhealthy diet and physical inactivity. NAFLD is an umbrella term, which encompasses various levels of hepatic disease from fat accumulation to cirrhosis. Fatty liver (simple steatosis) is an extremely common condition. 10-30% of individuals with steatosis develop some level of hepatic inflammation; namely non-alcoholic steatohepatitis (NASH). Approximately a third of patients with persistent inflammation deposit extracellular matrix proteins in the liver; known as hepatic fibrosis. Progressive scarring of the liver leads to cirrhosis. Therapeutic strategies for NAFLD are limited. Lifestyle modifications (dietary alterations and exercise) are recommended in all stages of NAFLD. NAFLD pathogenesis is not completely elucidated; numerous factors including carbohydrate-lipid metabolism, inflammation, innate immunity and fibrogenesis are involved at various stages of the clinical spectrum. In NASH, inflammation typically contains immune cells. However, it remains unknown how hepatic injury evolves to inflammation; the current theory also proposes the involvement of non-hepatic factors such as adipocyte (fat cells)-driven mediators, gut microbiota and other gut-driven factors. Progression from hepatic lipid deposition to inflammation and cirrhosis follows a substantially variable course. It has been estimated that less than 10% of patients develop CLD. Individual variability for disease progression is partly controlled by environmental factors and genetic background. Moreover, we previously demonstrated that heritable epigenetic modifications could modify susceptibility to CLD. More specifically, liver injury in the ancestors generated adaptive response and attenuated liver disease in the offspring. The associated epigenetic reprogramming, altered CpG methylation and histone marks, was also demonstrated in offspring livers. Currently it is not known if epigenetic signatures could dictate immune cell response and alter disease susceptibility in NAFLD. In this project we tested the hypothesis that lymphocyte subsets are epigenetically programmed into inflammatory state in NASH. We investigated the epigenetic mechanisms controlling hepatic inflammation, particularly NK and NKT immune cells, in NASH.
