Abstract
Liver fibrosis is an essential component of chronic liver disease (CLD) and hepatocarcinogenesis. The fibrotic stroma is a consequence of sustained liver damage combined with exacerbated extracellular matrix (ECM) accumulation. In this context, activation of hepatic stellate cells (HSCs) plays a key role in both initiation and perpetuation of fibrogenesis. These cells suffer profound remodeling of gene expression in this process. This review is focused on the epigenetic alterations participating in the transdifferentiation of HSCs from the quiescent to activated state. Recent advances in the field of DNA methylation and post-translational modifications (PTM) of histones (acetylation and methylation) patterns are discussed here, together with altered expression and activity of epigenetic remodelers. We also consider recent advances in translational approaches, including the use of epigenetic marks as biomarkers and the promising antifibrotic properties of epigenetic drugs that are currently being used in patients.
Highlights
Liver cancer is a major health problem worldwide causing more than 700,000 deaths annually [1]
Hepatocellular carcinoma (HCC) usually develops on the background of chronic liver disease (CLD), a pathological process that involves the progressive and sustained destruction and self-regeneration of the liver parenchyma leading to fibrosis and cirrhosis, and in the end stage, the development of cancer
We found that G9a and DNMT1 inhibition reduces DNA and H3K9 methylation levels in the promoter region of PPARγ, indicating that both G9a and DNMT1 might cooperate in the repression of this gene when hepatic stellate cells (HSCs) activate
Summary
Liver cancer is a major health problem worldwide causing more than 700,000 deaths annually [1]. Following liver injury, HSCs become activated, acquiring a phenotype characterized by the loss of retinoid droplets, increased proliferation and contractile activity, and the release of proinflammatory, profibrogenic, and promitogenic cytokines [8,10,13] How all these coordinated changes are globally orchestrated in these cells is still unknown. It was demonstrated that activated HSCs can return to the quiescent state upon resolution of chronic liver injury [15,16] These findings suggest that epigenetic mechanisms might be crucial in this process, controlling the cellular plasticity of HSCs and fibrogenesis. Epigenetic events that control HSC activation and function are highly dynamic processes and the phenotypic conversion requires changes in expression of hundreds of different genes [19]. We summarize what is known about the most relevant epigenetic mechanisms controlling HSC transdifferentiation and hepatic fibrogenesis
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