Abstract
Alcoholic liver disease (ALD), a disorder caused by excessive alcohol consumption is a global health issue. More than two billion people consume alcohol in the world and about 75 million are classified as having alcohol disorders. ALD embraces a wide spectrum of hepatic lesions including steatosis, alcoholic steatohepatitis (ASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). ALD is a complex disease where environmental, genetic, and epigenetic factors contribute to its pathogenesis and progression. The severity of alcohol-induced liver disease depends on the amount, method of usage and duration of alcohol consumption as well as on age, gender, presence of obesity, and genetic susceptibility. Genome-wide association studies and candidate gene studies have identified genetic modifiers of ALD that can be exploited as non-invasive biomarkers, but which do not completely explain the phenotypic variability. Indeed, ALD development and progression is also modulated by epigenetic factors. The premise of this review is to discuss the role of genetic variants and epigenetic modifications, with particular attention being paid to microRNAs, as pathogenic markers, risk predictors, and therapeutic targets in ALD.
Highlights
Chronic alcohol consumption is one of the leading causes of mortality worldwide [1]
Alcoholic liver disease (ALD) embraces a wide spectrum of hepatic lesions including steatosis, alcoholic steatohepatitis (ASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC)
MiR-21 was shown to target the 3 UTRs of FAS ligand G (FASLG) and death receptor 5 (DR5) whose expression was downregulated by ethanol. miR-21 is induced with ethanol exposure via IL6/signal transducer and activator of transcription 3 (STAT3) signaling and targets extrinsic apoptotic mediators like FASLG and DR5 in order to prevent hepatic cells apoptosis and to favor liver regeneration in ALD [128]
Summary
Chronic alcohol consumption is one of the leading causes of mortality worldwide [1]. According to the World Health Organization (WHO), 2.3 billion people consume alcohol in the world and about 75 million are classified as having alcohol disorders [2]. Alcoholic liver disease (ALD) embraces a broad spectrum of hepatic lesions including steatosis, alcoholic steatohepatitis (ASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) [4]. NADH is re-oxidized to NAD+ in the mitochondria generating reactive oxygen species (ROS) which can affect lipid peroxidation and DNA mutagenesis Another enzyme involved in ethanol metabolism is the Cytochrome P450 2E1(CYP2E1) which is induced by chronic alcohol consumption [15] and catalyzes ethanol oxidation to acetaldehyde by generating a significant amount of ROS, triggers of oxidative stress and inflammation. Acetaldehyde seems to be involved in steatosis development which occurs in 90% of alcohol abusers and in alcohol-related fibrogenesis by enhancing synthesis of collagen and transforming growth factor beta (TGFβ) secretion in hepatic stellate cells (HSCs) [20,21]. Higher levels of lipopolysaccharides (LPS) in ALD patients promote cancer stem cells proliferation [24]
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