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

Felix O'Farrell; Benjamin Aleyakpo; Rima Mustafa; Xiyun Jiang; Rui Climaco Pinto; Paul Elliott; Ioanna Tzoulaki; Abbas Dehghan; Samantha H Y Loh; Jeff W Barclay; L Miguel Martins; Raha Pazoki

doi:10.1038/s41598-023-47371-7

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

Sci Rep. 2023 Nov 23;13(1):20616. doi: 10.1038/s41598-023-47371-7.

Authors

Felix O'Farrell^#¹, Benjamin Aleyakpo^#², Rima Mustafa^#^{3

4}, Xiyun Jiang^#¹, Rui Climaco Pinto^#^{3

5}, Paul Elliott^{3

4

5

6

7

8}, Ioanna Tzoulaki^{3

9}, Abbas Dehghan^{3

4

5}, Samantha H Y Loh¹⁰, Jeff W Barclay¹¹, L Miguel Martins¹⁰, Raha Pazoki^{12

13

14}

Affiliations

¹ Cardiovascular and Metabolic Research Group, Division of Biosciences, Department of Life Sciences, College of Health and Life Sciences, Brunel University, London, UB8 3PH, UK.
² The Francis Crick Institute, London, NW1 1AT, UK.
³ Department of Epidemiology and Biostatistics, School of Public Health, St Mary's Campus, Imperial College London, Norfolk Place, London, W2 1PG, UK.
⁴ UK Dementia Research Institute, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.
⁵ MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, St Mary's Campus, Imperial College London, Norfolk Place, London, W2 1PG, UK.
⁶ British Heart Foundation Centre of Research Excellence, Imperial College London, Du Cane Road, W12 0NN, UK.
⁷ National Institute for Health Research, Imperial Biomedical Research Centre, Imperial College London, Exhibition Road, London, SW7 2AZ, UK.
⁸ Health Data Research UK at Imperial College London, Exhibition Road, London, SW7 2AZ, UK.
⁹ Centre for Systems Biology, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
¹⁰ MRC Toxicology Unit, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge, CB2 1QR, UK.
¹¹ Department of Molecular Physiology and Cell Signalling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 3BX, UK.
¹² Cardiovascular and Metabolic Research Group, Division of Biosciences, Department of Life Sciences, College of Health and Life Sciences, Brunel University, London, UB8 3PH, UK. [email protected].
¹³ Department of Epidemiology and Biostatistics, School of Public Health, St Mary's Campus, Imperial College London, Norfolk Place, London, W2 1PG, UK. [email protected].
¹⁴ Division of Biomedical Sciences, Department of Life Sciences, College of Health and Life Sciences, Brunel University, London, UB8 3PH, UK. [email protected].

^# Contributed equally.

Abstract

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.

MeSH terms

Alcohol Drinking / genetics
Animals
Caenorhabditis elegans* / genetics
Drosophila melanogaster* / genetics
Ethanol / metabolism
Humans
Lipid Metabolism* / genetics
Liver / metabolism
Liver Cirrhosis / pathology
Liver Diseases, Alcoholic* / metabolism

Substances

Ethanol
WD repeat containing planar cell polarity effector

Abstract

MeSH terms

Substances

Grants and funding