Evidence for Involvement ofWDPCPGene in Alcohol Consumption, Lipid Metabolism, and Liver Cirrhosis

Abstract

AbstractAlcohol consumption continues to cause a significant health burden globally. The advent of genome-wide association studies has unraveled many genetic loci associated with alcohol consumption. However, the biological effect of these loci and the pathways involved in alcohol consumption and its health consequences such as alcohol liver disease (ALD) remain to be elucidated. We combined human studies with model organismsDrosophila melanogasterandCaenorhabditis elegansto shed light on the molecular mechanisms underlying alcohol consumption and the health outcomes caused by alcohol intake. Using genetics and metabolite data within the Airwave study, a sample of police forces in the UK, we performed several analyses to identify changes in circulating metabolites that are triggered by alcohol consumption. We selected a set of genes annotated to genetic variants that are (1) known to be implicated in alcohol consumption, (2) are linked to liver function, and (3) are associated with expression (cis-eQTL) of their annotated genes. We used mutations and/or RNA interference (RNAi) to suppress the expression of these genes inC. elegansandDrosophila. We examined the effect of this suppression on ethanol consumption and on the sedative effects of ethanol. We also investigated the alcohol-induced changes in triacylglycerol (TGA) levels inDrosophilaand tested differences in locomotion ofC. elegansafter acute exposure to ethanol. In human population, we found an enrichment of the alcohol-associated metabolites within the linoleic acid (LNA) and alpha linolenic acid (ALA) metabolism pathway. We further showed the effect ofACTR1BandMAPTon locomotionin C. elegansafter exposure to ethanol. We demonstrated that three genes namelyWDPCP, TENM2andGPN1modify TAG levels inDrosophila. Finally, we showed that gene expression ofWDPCPin human population is linked to liver fibrosis and liver cirrhosis. Our results underline the impact of alcohol consumption on metabolism of lipids and pinpointsWDPCPas a gene with potential impact on fat accumulation upon exposure to ethanol suggesting a possible pathway to ALD.