Abstract
Non-alcoholic fatty liver disease (NAFLD) is a complex disease that is affected by genetic predisposition and epigenetic modification. Deregulation of epigenetic pathways is now recognized as a frequent event in NAFLD, and understanding the mechanistic roles of these epigenetic factors may lead to new strategies for NAFLD treatment. Enhancer of zeste homolog 2 (EZH2) catalyzes methylation on Lys 27 of histone H3, which leads to chromatin compaction and gene silencing. EZH2 regulates embryonic development and cell lineage determination and is related to many human diseases. Recent studies show that EZH2 has critical roles in liver development, homeostasis, and regeneration. Moreover, aberrant activation of EZH2 promotes NAFLD progression. Several EZH2 inhibitors have been developed and studied both in vitro and in clinical trials. In this review, we summarize our current understanding of the role of EZH2 in NAFLD and highlight its potential as a novel therapeutic target for NAFLD treatment.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide [1]
Vella et al [81] showed that Enhancer of zeste homolog 2 (EZH2) is down-regulated both in livers from NAFLD rats and in HepG2 cells treated with free fatty acid
EZH2 has a key role in liver development and homeostasis, and abnormal activation of EZH2 can lead to NAFLD progression (Figure 2)
Summary
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide [1]. Initial theories for the pathogenesis of NAFLD were based on a two-hit hypothesis According to this hypothesis, hepatic accumulation of lipid (the first hit) increases the susceptibility of the liver to further insults mediated by second hits. Hepatic accumulation of lipid (the first hit) increases the susceptibility of the liver to further insults mediated by second hits These second hits, such as inflammatory cytokines, mitochondrial dysfunction, and oxidative stress, lead to steatohepatitis and fibrosis [4,5]. Current NAFLD management includes diet and lifestyle changes for weight loss, management of metabolic risk factors, and pharmacological treatment [13]. The purpose of these treatments is to prevent NAFLD-associated complications [14]. We highlight EZH2 as a potential target for NAFLD therapy
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