Fatty Liver Disease
Non-alcoholic Fatty Liver Disease is a major risk factor for advanced liver injuries such as steatohepatitis, fibrosis and cirrhosis. Hepatic steatosis or fatty liver is characterized by an intracellular accumulation of triglycerides that is the result of an imbalance in lipid metabolism consequent on obesity with an excess in dietary carbohydrates and circulating fatty acids, or of hepatitis C virus (HCV) infection. Fatty acids are stored in triglycerides at a higher rate and they are burned at a slower rate. Steatosis, as seen in 90% of obese people, is now considered to be the hepatic component of the metabolic syndrome which includes diabetes and hypertension. In 10-15% of cases hepatic steatosis can progress to nonalcoholic steatohepatitis (NASH), a precursor of cirrhosis and hepatocellular carcinoma (HCC).
Current areas of research
The Group is currently looking at three particular areas of work:
1. The epigenetic mechanisms in Non-alcoholic Fatty Liver Disease
Alterations in hepatocyte metabolism and proliferation during steatosis and HCC are triggered by changes in gene transcriptional patterns, which in turn are governed by epigenetic mechanisms, such as DNA methylation, histone deacetylation and the incorporation of histone variants in the place of canonical histones. One protein that regulates chromatin compaction, currently under study, is called macroH2A1. This is a large histone that can regulate gene transcription in the liver. MacroH2A1 is present in 2 isoforms, macroH2A1.1 and macroH2A1.2, generated upon alternative RNA splicing.
MacroH2A1 is a regulator of hepatic fat accumulation and we have shown that its absence worsens hepatic steatosis and systemic sugar imbalances in a high fat diet. This could be due to a direct effect of macroH2A1 on chromatin structure and on the expression of key lipidogenic genes. Ongoing work shows that the ratio between the expression levels of macroH2A1.1 and macroH2A1.2 isoforms varies on high fat diet and the two isoforms may regulate differentially gene expression.
2. The circadian clock in HCV related hepatic steatosis
Hepatocyte functions including lipid metabolism and accumulation show fluctuations over each 24 hour period. At the cellular level this rhythm is driven by a molecular clock comprised of a translational-transcriptional feedback loop realized by a set of genes, called core clock genes, coding for proteins that in turn suppress gene expression in a cycle that completes itself each day. Disruption of genes of the cellular circadian clock causes hepatic steatosis and shift workers are known to have a higher incidence of hepatic steatosis and diabetes. We have shown that HCV triggers hepatic steatosis by modulating growth factor signalling. The hepatic steatosis associated with HCV infection may also have mechanistic interactions with the circadian clock.
Using cell culture systems, molecular biology and imaging techniques the aim is to shed light on the complex molecular interplay between viral infection, expression/activity of clock genes and the emergence of hepatic steatosis.
3. Cardiac consequences of hepatic steatosis
Hepatic steatosis is a major risk factor for cardiac events including arrhythmia and infarction. Cardiovascular diseases (CVD) in general are more common than liver events in the increased morbidity/mortality of steatosis.
The mechanism whereby steatosis causes this increased risk of cardiovascular events and death has not yet been established. Understanding the signalling mechanisms involved in the link between liver and heart is important in identifying new therapeutic approaches and to cluster patients at risk. Studies are underway to enable us to understand if the response to cardiac stress is worsened or not by the degree of severity of lipid accumulation and inflammation.