Abstract
ABSTRACTNon-alcoholic fatty liver disease (NAFLD) is now the commonest cause of liver disease in developed countries affecting 25–33% of the general population and up to 75% of those with obesity. Recent data suggest that alterations in DNA methylation may be related to NAFLD pathogenesis and progression and we have previously shown that dynamic changes in the cell lineage identifier 5-hydroxymethylcytosine (5hmC) may be important in the pathogenesis of liver disease. We used a model of diet-induced obesity, maintaining male mice on a high-fat diet (HFD) to generate hepatic steatosis. We profiled hepatic gene expression, global and locus-specific 5hmC and additionally investigated the effects of weight loss on the phenotype. HFD led to increased weight gain, fasting hyperglycaemia, glucose intolerance, insulin resistance and hepatic periportal macrovesicular steatosis. Diet-induced hepatic steatosis associated with reversible 5hmC changes at a discrete number of functionally important genes. We propose that 5hmC profiles are a useful signature of gene transcription and a marker of cell state in NAFLD and suggest that 5hmC profiles hold potential as a biomarker of abnormal liver physiology.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is the commonest cause of liver disease in developed countries, affecting 25–33% of the general population and up to 75% of those with obesity [1,2,3,4]
Further evidence in support of a role for DNA methylation in NAFLD comes from studies in mice showing that dietary restriction of methyl donors or impairment of methyl donor metabolism causes liver injury similar to NAFLD [29,30] and dietary methyl donor supplementation appears to protect rodents from high fat/ sucrose diet-induced hepatic steatosis [12]
Using a genome-wide analysis of liver 5hmC in a mouse model of diet-induced obesity (DIO) we show that that hepatic steatosis associates with reversible 5hmC changes at a discrete number of functionally important genes
Summary
Non-alcoholic fatty liver disease (NAFLD) is the commonest cause of liver disease in developed countries, affecting 25–33% of the general population and up to 75% of those with obesity [1,2,3,4]. The inter-individual variability in the risk of progression, coupled with a lack of understanding of underlying mechanisms has limited the development of effective biomarkers of risk and therapeutic interventions. Recent data using both genome-wide and candidate gene analysis in human liver biopsy specimens have identified alterations in DNA methylation (5-methylcytosine, 5mC) over promoter and genic regions of functionally relevant genes and pathways in association with disease state, suggesting that epigenetic dysregulation may play a role in the pathogenesis and progression of NAFLD [8,9,10].
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