G-protein αq gene expression plays a role in alcohol tolerance in <i>Drosophila melanogaster</i>

Aleyakpo, Benjamin; Umukoro, Oghenetega; Kavlie, Ryan G.; Ranson, Daniel; Thompsett, Andrew R.; Corcoran, Olivia; Casalotti, Stefano O.

doi:10.1177/2398212819883081

Cited by 3 publications

(2 citation statements)

References 39 publications

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“…Drosophila Ethanol sedation Assay. Fly sedation assay was performed as previously described 17 . Briefly, 8 flies were transferred to a 25mm x 95mm transparent plastic vial in between two cotton plugs.…”

Section: Methodsmentioning

confidence: 99%

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

OFarrell

Aleyakpo

Mustafa

et al. 2023

Preprint

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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.

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Section: Methodsmentioning

confidence: 99%

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

OFarrell

Aleyakpo

Mustafa

et al. 2023

Preprint

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show abstract

“…Drosophila Ethanol sedation Assay. Fly sedation assay was performed as previously described 19 . Brie y, 8 ies were transferred to a 25mm x 95mm transparent plastic vial in between two cotton plugs.…”

Section: Methods -Populationmentioning

confidence: 99%

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

Pazoki

O’Farrel

Aleyakpo

et al. 2023

Preprint

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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.

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Evidence for involvement of the alcohol consumption WDPCP gene in lipid metabolism, and liver cirrhosis

O’Farrell,

Aleyakpo,

Mustafa

et al. 2023

Sci Rep

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Biological pathways between alcohol consumption and alcohol liver disease (ALD) are not fully understood. We selected genes with known effect on (1) alcohol consumption, (2) liver function, and (3) gene expression. Expression of the orthologs of these genes in Caenorhabditis elegans and Drosophila melanogaster was suppressed using mutations and/or RNA interference (RNAi). In humans, association analysis, pathway analysis, and Mendelian randomization analysis were performed to identify metabolic changes due to alcohol consumption. In C. elegans, we found a reduction in locomotion rate after exposure to ethanol for RNAi knockdown of ACTR1B and MAPT. In Drosophila, we observed (1) a change in sedative effect of ethanol for RNAi knockdown of WDPCP, TENM2, GPN1, ARPC1B, and SCN8A, (2) a reduction in ethanol consumption for RNAi knockdown of TENM2, (3) a reduction in triradylglycerols (TAG) levels for RNAi knockdown of WDPCP, TENM2, and GPN1. In human, we observed (1) a link between alcohol consumption and several metabolites including TAG, (2) an enrichment of the candidate (alcohol-associated) metabolites within the linoleic acid (LNA) and alpha-linolenic acid (ALA) metabolism pathways, (3) a causal link between gene expression of WDPCP to liver fibrosis and liver cirrhosis. Our results imply that WDPCP might be involved in ALD.

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G-protein αq gene expression plays a role in alcohol tolerance in Drosophila melanogaster

Cited by 3 publications

References 39 publications

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

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

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

Evidence for involvement of the alcohol consumption WDPCP gene in lipid metabolism, and liver cirrhosis

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