Genetic and Epigenetic Modifiers of Alcoholic Liver Disease

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.

Keywords: MBOAT7; PNPLA3; TM6SF2; alcoholic liver disease; epigenetics; intestinal permeability; microRNAs; tight junctions.

Figure 1

PNPLA3, TM6SF2, and MBOAT7: the genetic modifiers of ALD. (A) The Patatin-like phospholipase domain-containing 3 (PNPLA3) is an intracellular membrane lipase, localized on the surface of lipid droplets in hepatocytes where catalyzed the hydrolysis of triglycerides (TG). The Transmembrane 6 superfamily member 2 (TM6SF2) is involved in very low-density lipoprotein (VLDL) secretion, whereas the Membrane bound O-acyltransferase domain containing 7 (MBOAT7) catalyzes the transfers of polyunsaturated fatty acids, such as arachidonoyl-CoA to lysophospholipids, thus maintaining the fluidity of membranes. The PNPLA3, TM6SF2 and MBOAT7 proteins are represented in green and their physiological functions are indicated by green arrows (B). The prolonged ethanol (Et-OH) exposure impairs insulin sensitivity, enhancing the flux of free fatty acids from adipose tissue and de novo lipogenesis, induced by sterol regulatory element-binding protein (SREBP-1c). These events lead to fat accumulation which may be exacerbated by the presence of genetic modifiers. The PNPLA3 148M variant increases hepatic TG content upon accumulation of the mutant protein on the surface of lipid droplets. Indeed, 148M proteins interfere with lipid remodeling in fatty-laden hepatocytes and inhibit the activity of other lipases, reducing TG turnover and dismissal. Moreover, the 148M variant impairs the amount of VLDL released, exacerbating fat deposition. The TM6SF2 E167K variant impairs physiological VLDL secretion and affects cholesterol metabolism and TG synthesis. The intronic rs641738 variant in MBOAT7 reduces membrane fluidity and dynamism by altering phospholipid acyl-chains remodeling and enhancing the amount of free arachidonic acid (AA), triggering hepatic inflammation. The PNPLA3, TM6SF2 and MBOAT7 mutated proteins are coloured in red and their aberrant effects are highlighted by red arrows. Dashed arrows indicate the bidirectional flux of molecules from extracellular to intracellular spaces and viceversa. The combined effect of PNPLA3, TM6SF2 and MBOAT7 genetic variants may predispose to a worsening risk of progressive liver damage and HCC (B). Modified by Dongiovanni, P., Int. J. Mol. Sci. 2017.

Figure 2

Role of miRNAs in progressive ALD. Environmental, genetic, and epigenetic factors along with excessive alcohol abuse contribute to ALD pathogenesis and progression. In this figure, we reported a schematic illustration of candidate miRNAs demonstrated to affect Et-OH-induced liver injury in both different hepatic and small intestinal cell types: hepatocytes, inflammatory cells (i.e., Kupffer cells), and enterocytes. Several miRNAs can be secreted into the circulation through exosomes and microvesicles triggering steatosis onset, inflammation, fibrosis, and carcinogenesis. Increasing intestinal expression of miRNAs (miR-122 and miR-212) affect gut barrier integrity by loosening the tight junctions of Zonula Occludens 1 (ZO-1) and enhanced Lipopolysaccharides (LPS) release into the circulation. LPS induced Toll-like Receptor 4 (TLR4) activation in hepatic Kupffer cells and macrophages. miRNAs even support hepatic inflammation via NF-kB; IL6/STAT3 signaling and oxidative stress (i.e., TNF-α and ROS production) and can contribute to the worsening of hepatic injury by a strict but firm regulation of cell–cell cross-talk. Circulating miRNAs can be easily detected in blood circulation as diagnostic, prognostic, and predictive biomarkers.