Evidence for Involvement of the Alcohol Consumption WDPCP Gene in Lipid Metabolism, and Liver Cirrhosis

Abstract

Alcohol 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, biological effects of these loci and 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 organisms Drosophila melanogaster and Caenorhabditis elegans to shed light on molecular mechanisms underlying alcohol consumption and the health outcomes caused by alcohol intake. Using genetics and metabolite data within the Airwave study, a longitudinal study to investigate the health of employees of police forces in the UK, we performed several analyses to identify changes in circulating metabolites that are triggered by alcohol consumption and found an enrichment of the alcohol-associated metabolites within the linoleic acid (LNA) and alpha-linolenic acid (ALA) metabolism pathways. We identified evidence of a potential causal relationship between alcohol consumption with several triradylglycerols (TAGs) and diradylglycerols (DAGs), a fatty ester (CAR DC18:1), an sphingomyelin (SM 40:2;O2), and an alkaloid (Piperine). We selected a set of genes annotated to genetic variants that (1) are known to be implicated in alcohol consumption, (2) are linked to liver function, and (3) are associated with the expression (cis-eQTL) of their annotated genes. We used mutations and/or RNA interference (RNAi) to suppress the expression of these genes in C. elegans and Drosophila. Testing the differences in locomotion of C. elegans showed that RNAi knockdown of ACTR1B and MAPT reduced locomotion rate in C. elegans after exposure to ethanol. We showed that RNAi knockdown of several genes (WDPCP, TENM2, GPN1, ARPC1B, SCN8A) in Drosophila changed the sedative effect of ethanol whilst RNAi knockdown of TENM2 reduced ethanol consumption. We also investigated alcohol-induced changes in TAG levels in Drosophila and demonstrated that RNAi knockdown of WDPCP, TENM2 and GPN1 reduce TAG levels. Finally, using publicly available human data, we showed that gene expression of WDPCP is linked to liver fibrosis and liver cirrhosis. Our results underline the impact of alcohol consumption on the metabolism of lipids and pinpoint WDPCP as a gene with a potential impact on lipid accumulation upon exposure to ethanol suggesting a possible pathway to ALD.