The Role of Epigenetic Changes in the Progression of Alcoholic Steatohepatitis

Abstract

Alcoholic steatohepatitis (ASH) is a progression hepatitis with severe fatty liver and its mortality rate for 30-days in patients are over 30%. Additionally, ASH is well known for one-fifth all alcoholic related liver diseases in the world. Excessive chronic alcohol consumption is one of the most common causes of the progression of ASH and is associated with poor prognosis and liver failure. Alcohol abuse dysregulates the lipid homeostasis and causes oxidative stress and inflammation in the liver. Consequently, metabolic pathways stimulating hepatic accumulation of excessive lipid droplets are induced. Recently, many studies have indicated a link between ASH and epigenetic changes, showing differential expression of alcohol-induced epigenetic genes in the liver. However, the specific mechanisms underlying the pathogenesis of ASH remain elusive. Thus, we here summarize the current knowledge about the roles of epigenetics in lipogenesis, inflammation, and apoptosis in the context of ASH pathophysiology. Especially, we highlight the latest findings on the roles of Sirtuins, a conserved family of class-III histone deacetylases, in ASH. Additionally, we discuss the involvement of DNA methylation, histone modifications, and miRNAs in ASH as well as the ongoing efforts for the clinical translation of the findings in ASH-related epigenetic changes.

Keywords: DNA methylation; alcoholic steatohepatitis; epigenetics; miRNAs; sirtuins.

FIGURE 1

Specific roles of Sirtuins and DNA methylation in ASH. (A) Numerous SIRT-modulated mechanisms mainly regulate hepatic inflammation via inactivation of Kupffer cells and reduce lipogenesis during ASH. Sirt6 shows protective effects by normalizing the ethanol metabolism and increasing antioxidant components via enhancement of MTF1 acylation in the nucleus. Sirt3 enhances the mitochondrial apoptotic signals and prevents autophagy. (B) The role of DNA methylation in ASH. Lipid-droplet accumulation in the liver during ASH is suppressed by regulating factors associated with the lipid homeostasis or extracellular matrix via the Ufmylation pathways in hepatocytes and myofibroblasts. In plasma DNA, DNA methylation also regulates PDGFα expression during ASH.

FIGURE 2

Overview of the epigenetic changes in ASH. Metabolic pathways regulated by acetaldehyde, cytokine, and FFA are induced by excessive alcohol drinking and chronic over- nutrition. Excessive alcohol drinking and chronic over-nutrition synergistically induces ASH progression via activating several different signaling pathways in the liver, including epigenetic changes. Additionally, hepatic cytokine and FFA levels of cytokines are induced as a result of the associated multiple organ damages, such as those in the adipose tissue, brain, intestines, and muscles. Eventually, this pathway increases hepatic inflammation and hepatocyte lipotoxicity, which result in the stimulation of ASH.