The WDPCP gene in alcohol consumption, lipid metabolism, and liver cirrhosis

This study investigates the role of the WDPCP gene in alcohol consumption, lipid metabolism, and liver cirrhosis using genetic studies in model organisms and human data analysis.

In this study, we studied genes affecting alcohol consumption, liver function, and gene expression in C. elegans and Drosophila using mutations and RNA interference (RNAi).

We found changes in locomotion, sedative effects, ethanol consumption, and triacylglycerols (TAG) levels. In humans, we linked alcohol consumption to metabolites and liver disease, suggesting WDPCP's involvement in alcohol liver disease (ALD).

Why we need to understand the mechanisms of alcohol liver disease

This research project is essential because the biological pathways linking alcohol consumption to alcohol liver disease (ALD) are not fully understood. By identifying and studying genes that affect alcohol consumption, liver function, and gene expression, researchers can uncover the mechanisms behind ALD. This knowledge can lead to better prevention, diagnosis, and treatment strategies for ALD.

The project contributes to broader societal goals by addressing ALD's significant public health burden. Understanding these pathways can inform public health policies, reduce healthcare costs, and improve the quality of life for individuals affected by alcohol-related liver diseases. It can also help develop targeted therapies and interventions, ultimately reducing the incidence and severity of ALD.

Our research project stands out due to its comprehensive approach, combining genetic studies in model organisms (C. elegans and Drosophila) with human association, pathway, and Mendelian randomisation analyses. By using both C. elegans and Drosophila, the study leverages the strengths of different model organisms to uncover genetic and metabolic pathways relevant to ALD. The use of RNA interference (RNAi) and mutations to suppress gene expression in these organisms provides insights into the functional roles of specific genes in alcohol consumption and liver function.

The integration of human genetic data with findings from model organisms allows for a more comprehensive understanding of how these genes and pathways operate in humans. The study's focus on metabolic changes and the identification of specific metabolites linked to alcohol consumption and liver disease adds a layer of biochemical understanding that is often missing in genetic studies.

Our approach

The biological pathways between alcohol consumption and alcohol liver disease (ALD) are not fully understood. We selected genes with known effects on alcohol consumption, liver function, and 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 C. elegans, we found a reduction in locomotion rate after exposure to ethanol for RNAi knockdown of ACTR1B and MAPT. In Drosophila, we observed changes in the sedative effect of ethanol for RNAi knockdown of WDPCP, TENM2, GPN1, ARPC1B, and SCN8A, a reduction in ethanol consumption for RNAi knockdown of TENM2, and a reduction in triacylglycerols (TAG) levels for RNAi knockdown of WDPCP, TENM2, and GPN1.

In humans, association analysis, pathway analysis, and Mendelian randomisation analysis were performed to identify metabolic changes due to alcohol consumption. We observed a link between alcohol consumption and several metabolites, including TAG, and an enrichment of the candidate (alcohol-associated) metabolites within the linoleic acid (LNA) and alpha-linolenic acid (ALA) metabolism pathways. Additionally, we found a causal link between gene expression of WDPCP and liver fibrosis and liver cirrhosis. Our results imply that WDPCP might be involved in ALD.

Understanding the role of the WDPCP gene in alcohol consumption, lipid metabolism, and liver cirrhosis will provide valuable insights into the mechanisms behind ALD. This research could lead to improved prevention, diagnosis, and treatment strategies for ALD, ultimately reducing the public health burden and improving the quality of life for affected individuals.