Project ID CM-HD2024_39


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Department of Inflammation BiologyWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Department of Inflammation BiologyWebsite

Lipids as immunometabolic mediators in liver failure

Death from liver disease is rising in all age groups with significant impact on healthcare systems. In liver failure patients often die of infection due to dysfunctional immune systems and are difficult to treat in intensive care units.

Our group has developed an interest and global expertise in the control of immunity in liver failure by lipids describing phospholipid control of monocytes. These molecules turn off anti-inflammatory responses and are the basis of future therapies to restore immune function and prevent patients dying of sepsis. This project aims to interrogate how lipids control immune and liver cells and test therapies for future clinical trials. It utilises a broad gamut of immunometabolism techniques including cell culture, flow cytometry, metabonomics, transciptomics, ELISA and advanced statistics.

In year 1-2 the student will learn lipid biology, metabonomics and statistics and identify lipid pathways of interest and choose the target cell(s) of most relevance. They will also learn how to: a) isolate human hepatocytes from donor liver tissues (normal, and steatotic/fatty) unused/rejected for transplantation, b) in vitro maintenance of hepatocyte culture, c) carry out assays to assess the function and activity of hepatocytes including cell attachment, overall metabolic activity, urea synthesis (ammonia detoxification assay), albumin synthesis, and cytochrome P450 activity (drug metabolism assay).
In year 2-3 they will use cell culture and flow cytometry to determine the functional and phenotypic effects of lipids on immune and hepatic cells. This will also involve testing candidate drugs for immune restoration to form the basis of human experimental medicine clinical trials. The hepatocytes will be analysed at the molecular level to study the expression of key genes involved in lipid metabolism.
In year 3-4 transcriptomics of cells from year 2-3, pathway analysis and writing will be undertaken and immune cell/hepatocyte co-culture if time permits.

Representative Publications

Trovato FM, Zia R, Artru F, Mujib S, Jerome E, Cavazza A, Coen M, Wilson I,Holmes E, Morgan P, Singanayagam A, Bernsmeier C, Napoli S, Bernal W, Wendon J, Miquel R, Menon K, Patel VC, Smith J, Atkinson SR, Triantafyllou E, McPhail MJW. Lysophosphatidylcholines modulate immunoregulatory checkpoints in peripheral monocytes and are associated with mortality in people with acute liver failure. J Hepatol. 2023 Mar;78(3):558-573. doi: 10.1016/j.jhep.2022.10.031. Epub 2022 Nov 9. PMID: 36370949. Morrison MA, Artru F, Trovato FM, Triantafyllou E, McPhail MJ. Potential therapies for acute-on-chronic liver failure. Liver Int. 2023 Feb 17. doi: 10.1111/liv.15545. Epub ahead of print. PMID: 36800487. Artru F, McPhail MJW, Triantafyllou E, Trovato FM. Lipids in Liver Failure Syndromes: A Focus on Eicosanoids, Specialized Pro-Resolving Lipid Mediators and Lysophospholipids. Front Immunol. 2022 Mar 31;13:867261. doi: 10.3389/fimmu.2022.867261. PMID: 35432367; PMCID: PMC9008479.
Recent cases of acute hepatitis in children. Morgan PE, Mitry RR. Lancet. 2023 Mar 25;401(10381):996. doi: 10.1016/S0140-6736(23)00135-6. PMID: 36965969. Alginate microencapsulated human hepatocytes for the treatment of acute liver failure in children. Dhawan A, Chaijitraruch N, Fitzpatrick E, Bansal S, Filippi C, Lehec SC, Heaton ND, Kane P, Verma A, Hughes RD, Mitry RR. J Hepatol. 2020 May;72(5):877-884. doi: 10.1016/j.jhep.2019.12.002. Epub 2019 Dec 13. PMID: 31843649. Validation of Current Good Manufacturing Practice Compliant Human Pluripotent Stem Cell-Derived Hepatocytes for Cell-Based Therapy. Blackford SJI, Ng SS, Segal JM, King AJF, Austin AL, Kent D, Moore J, Sheldon M, Ilic D, Dhawan A, Mitry RR, Rashid ST. Stem Cells Transl Med. 2019 Feb;8(2):124-137. doi: 10.1002/sctm.18-0084. Epub 2018 Nov 19. PMID: 30456803; PMCID: PMC6344902.