Reversing Epigenetic Alterations Caused by Alcohol: A Promising Therapeutic Direction for Alcoholic Liver Disease

Abstract

Alcoholic liver disease (ALD), a liver function disorder caused by excessive alcohol intake, is a serious threat to global public health and social development. Toxic metabolites and reactive oxygen species produced during the metabolism of alcohol can alter the epigenetic state including DNA methylation, histone modifications, and expression of microRNAs. Epigenetic alterations can conversely involve various signaling pathways, which could contribute to the initiation and progression of ALD. To elucidate the relationship between epigenetic alterations and alcohol damage not only reinforces our understanding on pathogenesis of ALD, but also provides novel targets for clinical diagnosis, treatment, and drug research of ALD. In this review, we have summarized the research progress of epigenetic alterations and related mechanisms caused by alcohol in the pathogenesis of ALD. Considering the invertibility of epigenetic alterations, treatment of ALD through epigenetic modification with common less harmful compounds is also related.

Hepatic COX-2 expression protects mice from an alcohol-high fat diet-induced metabolic disorder by involving protein acetylation related energy metabolism

“…It has been reported that chromatin remodeling is involved in COX-2-induced cellular events, as evidenced by a recent study that demonstrates the DNA methylation of specific oncogenes in COX-2-overexpressing mice ( Chen et al, 2017 ). While recent studies suggesting that histone and mitochondrial protein acetylation in a high fat diet evoke protein hyper-acetylation are controversial ( Carrer et al, 2017 ; Choi & Friso, 2010 ; Meyer et al, 2018 ; Peterson et al, 2018 ), the contribution to the hyper-acetylation status from the ethanol diet is more widely accepted ( Choi & Friso, 2010 ; Jung & Metzger, 2015 ; Kriss et al, 2018 ; Lin et al, 2018 ; Zhong et al, 2010 ; Zhong & Lemasters, 2018 ). A recent approach using 13 C-labeled ethanol together with mass spectrometry in an ethanol binge drinking mouse model provided the quantitative evidence of histone hyper-acetylation status ( Kriss et al, 2018 ), and we would like to employ this method in our future studies to significantly improve our understanding of the critical steps in nutritional rerouting in dietary stress.…”

Epigenetics of alcohol-related liver diseases

“…The role of microRNA (miRNA) in the pathogenesis of ARLD has been reviewed extensively over the years. [14,35,[160][161][162][163][164]. Dysregulation of miRNAs in ARLD is linked to the development of steatosis (yellow circle), inflammation via recruitment of inflammatory cells (blue circle), fibrosis (blue lines) and HCC (green circle).…”

Mechanism and Therapeutic Opportunities of Histone Modifications in Chronic Liver Disease

“…In addition to the deacetylation function, SIRT1 promotes the conversion of the metabolite of ethanol acetic acid into acetyl-CoA, which acetylates histones under the catalysis of HATs (Sahar et al, 2014;Lin et al, 2018). Therefore, SIRT1 may be involved in the balance of gene silencing and activation in ALD via acetylation of histones.…”

“…However, acetaldehyde is rapidly oxidized to acetate under the catalysis of aldehyde dehydrogenase 2 (ALDH2) inside mitochondria, accompanied with NAD+ consumption and NADH production ( Osna et al, 2017 ). The pathogenesis of ALD is quite complex and results from the interaction of multiple mechanisms ( Lin et al, 2018 ; Sehrawat et al, 2020 ). The metabolism of ethanol in the liver produces abundant reactive oxygen species (ROS) and alters the balance between lipogenesis and fatty acid metabolism, leading to hepatic steatosis ( Xu et al, 2017 ).…”

“…Besides, many studies have demonstrated that the expression of HDAC is inhibited and is associated with increased hepatic histone acetylation after alcohol exposure ( Yeung et al, 2004 ; You et al, 2008 ; Kirpich et al, 2012 ). In addition to the deacetylation function, SIRT1 promotes the conversion of the metabolite of ethanol acetic acid into acetyl-CoA, which acetylates histones under the catalysis of HATs ( Sahar et al, 2014 ; Lin et al, 2018 ). Therefore, SIRT1 may be involved in the balance of gene silencing and activation in ALD via acetylation of histones.…”