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.

Epigenetics of alcohol-related liver diseases

“…[38] In the subsequent years numerous studies linked DNA-methylation and the development of alcohol related steatohepatitis. [39][40][41][42][43] More recently, a study uncovered a new axis consisting of FKBP5-YAP-TEAD1-CXCL1 connecting ethanol consumption and the development of steatohepatitis. [44] FK506-binding protein 51 (FKBP5) is a cochaperone protein that is involved in stress-related disorders.…”

“…Fibrosis is a common end pathway of many liver disease processes including ARLD. [43,[49][50][51] In a healthy liver, hepatic stellate cells (HSCs) are quiescent J o u r n a l P r e -p r o o f perisinusoidal cells, but in response to hepatic damage, HSCs undergo transdifferentiation into an extracellular matrix-depositing myofibroblastlike phenotype. [50,51] HSC transdifferentiation is mediated in part by DNA methylation.…”

Epigenetic Aspects and Prospects in Autoimmune Hepatitis

“…Studies in alcoholic liver disease (54,55) and non-alcoholic fatty liver disease (NAFLD) (220)(221)(222)(223)(224)(225)(226)(227)(228)(229) have emphasized the pervasive, interactive, and composite effects of epigenetic modifications in each disease. They have also indicated the needs to associate changes in disease expression to clinically relevant features and to explore the heritable and adaptive nature of the epigenetic modifications.…”

“…Salient epigenetic effects have already been identified in experimental models and patients with diverse liver diseases, including alcoholic steatohepatitis (54,55), non-alcoholic fatty liver disease (NAFLD) (56)(57)(58), primary biliary cholangitis (PBC) (59)(60)(61), primary sclerosing cholangitis (PSC) (62)(63)(64), cholangiocarcinoma (62,(65)(66)(67), hepatocellular cancer (68,69), and autoimmune hepatitis (21,70,71). They have also been implicated in various non-liver diseases, including systemic lupus erythematosus (SLE) (72,73), rheumatoid arthritis (74,75), systemic sclerosis (76,77), diverse neurodegenerative diseases (78), and various cancers (79)(80)(81)(82).…”

Mechanism and Therapeutic Opportunities of Histone Modifications in Chronic Liver Disease

“…The methylation of histones is regulated by the activity of histone methyltransferases (HMTs) and histone demethylases (HDMTs) ( Kim et al, 2021 ). HMTs catalyze the addition of methyl groups from S-adenosylmethionine (SAM) onto lysine and arginine residues of histones.…”