Epigenetic Marks May Regulate Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is an increasingly alarming health problem in the United States where it is estimated that up to 30% of the population has a fatty liver. Approximately 10% of NAFLD patients will progress in disease severity leading to inflammation and fibrosis and eventually more serious consequences such as cirrhosis or liver cancer. Better understanding the molecular and epigenetic changes in the liver driving disease progression could lead to better treatments.

Understanding how DNA methylation is altered in disease states such as NAFLD could lead to better insight into how key genes involved in the disease become activated. Scientists are currently seeking to identify how genes involved in liver disease might be regulated at an epigenetic level by DNA methylation. Better understanding of the early molecular switches that causes dysregulation of key genes involved in NAFLD could lead to better preventative measures or treatments.

A team of researchers at the Translational Genomics Research Institute in Phoenix, Arizona measured DNA methylation in liver biopsies of histologically-determined obese NAFLD patients with cirrhosis and compared the findings to samples from an obese control group without liver disease. Importantly, the researchers wanted to determine whether changes in DNA methylation was correlated with altered gene expression in the cirrhosis patients.

The researchers found a different pattern of DNA methylation of genes involved in reactive oxygen and reactive nitrogen species production, both of which are produced by immune cells during liver inflammation.

“Our findings showed statistically significant evidence for differential DNA methylation between fibrotic and normal tissue samples from obese individuals,” said Dr. Johanna DiStefano, who is a professor and head of the Translational Genomics Research Institute Diabetes and Fibrotic Disease Unit.

Genes involved in cell signaling pathways involved in lipid metabolism including FXR/RXR and LXR/RXR were also differentially expressed.

The authors compared the results of their study to four previous studies which sought to determine whether NAFLD was associated with altered DNA methylation in the liver and found key similarities including altered methylation of the AQP1, FGFR2, RBP5, and MGMT genes. AQP1 and FGFR2 are especially known to be upregulated in fibrotic liver tissue and these genes could represent new therapeutic targets.

The results of this study further drive home the idea that epigenetic regulation of gene expression is altered during the course of NAFLD and cirrhosis may be a result of aberrant expression of key genes involved in inflammation and lipid metabolism driven my epigenetic changes.

The authors suggested that it would be prudent to determine if genes in other tissues such as blood cells were differentially regulated during NAFLD. Currently, there are no definitive blood biomarkers for NAFLD. If NAFLD was associated with a unique epigenetic signature in peripheral blood cells, it is possible that diagnosis of the disease could be improved, potentially leading to earlier intervention and reduced burden of the long-term consequences of disease among the population.

Source:  Gerhard, Glenn S., et al. (2018) “Differentially methylated loci in NAFLD cirrhosis are associated with key signaling pathways.” Clinical Epigenetics 10. 93.

Reference: Steve Yozwiak “TGEN-Led Study Shows DNA Methylation Related to Liver Disease Among Obese Patients” Translational Genomics Research Institute. 18 Jul. 2018. Web.