OFarrell, F. | Search bioRxiv

bioRxiv2023

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

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, 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 organisms Drosophila melanogaster and Caenorhabditis elegans to 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 in C. elegans and Drosophila. 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 in Drosophila and tested differences in locomotion of C. elegans after 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 of ACTR1B and MAPT on locomotion in C. elegans after exposure to ethanol. We demonstrated that three genes namely WDPCP, TENM2 and GPN1 modify TAG levels in Drosophila. Finally, we showed that gene expression of WDPCP in human population is linked to liver fibrosis and liver cirrhosis. Our results underline the impact of alcohol consumption on metabolism of lipids and pinpoints WDPCP as a gene with potential impact on fat accumulation upon exposure to ethanol suggesting a possible pathway to ALD.

genetics↗

bioRxiv2020

Host autophagy mediates organ wasting and nutrient mobilization for tumor growth

During tumor growth - when nutrient and anabolic demands are high - autophagy supports tumor metabolism and growth through lysosomal organelle turnover and nutrient recycling1. Ras-driven tumors additionally invoke non-autonomous autophagy in the microenvironment to support tumor growth, in part through transfer of amino acids2-4. Here we uncover a third critical role of autophagy in mediating systemic organ wasting and nutrient mobilization for tumor growth using a well-characterized malignant tumor model in Drosophila melanogaster. Micro-computed X-ray tomography and metabolic profiling reveal that RasV12; scrib-/- tumors grow 10-fold in volume, while systemic organ wasting unfolds with progressive muscle atrophy, loss of body mass, -motility, -feeding and eventually death. Tissue wasting is found to be mediated by autophagy and results in host mobilization of amino acids and sugars into circulation. Natural abundance Carbon 13 tracing demonstrates that tumor biomass is increasingly derived from host tissues as a nutrient source as wasting progresses. We conclude that host autophagy mediates organ wasting and nutrient mobilization that is utilized for tumor growth.

cell biology↗