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Lookup NU author(s): Dr Jack LeslieORCiD, Amy Collins, Zosia Johnson, Jeremy French, Steven White, John Moir, Professor Derek MannORCiD, Professor Fiona OakleyORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 The Authors. Background and aims: Steatotic liver disease (SLD), which encompasses various causes of fat accumulation in the liver, is a major cause of liver fibrosis. Understanding the specific mechanisms of lipotoxicity, dysregulated lipid metabolism, and the role of different hepatic cell types involved in fibrogenesis is crucial for therapy development. Methods: We analysed liver tissue from SLD patients and 3 mouse models. We combined bulk/spatial lipidomics, transcriptomics, imaging mass cytometry (IMC) and analysis of published spatial and single-cell RNA sequencing (scRNA-seq) data to explore the metabolic microenvironment in fibrosis. Pharmacological inhibition of sphingolipid metabolism with myriocin, fumonisin B1, miglustat and D-PDMP was carried out in hepatic stellate cells (HSCs) and human precision cut liver slices (hPCLSs). Results: Bulk lipidomics revealed increased glycosphingolipids, ether lipids and saturated phosphatidylcholines in fibrotic samples. Spatial lipidomics detected >40 lipid species enriched within fibrotic regions, notably sphingomyelin (SM) 34:1. Using bulk transcriptomics (mouse) and analysis of published spatial transcriptomics data (human) we found that sphingolipid metabolism was also dysregulated in fibrosis at transcriptome level, with increased gene expression for ceramide and glycosphingolipid synthesis. Analysis of human scRNA-seq data showed that sphingolipid-related genes were widely expressed in non-parenchymal cells. By integrating spatial lipidomics with IMC of hepatic cell markers, we found excellent spatial correlation between sphingolipids, such as SM(34:1), and myofibroblasts. Inhibiting sphingolipid metabolism resulted in anti-fibrotic effects in HSCs and hPCLSs. Conclusions: Our spatial multi-omics approach suggests cell type-specific mechanisms of fibrogenesis involving sphingolipid metabolism. Importantly, sphingolipid metabolic pathways are modifiable targets, which may have potential as an anti-fibrotic therapeutic strategy.
Author(s): Gruevska A, Leslie J, Perpinan E, Maude H, Collins AL, Johnson S, Evangelista L, Sabey E, French J, White S, Moir J, Robinson SM, Alrawashdeh W, Thakkar R, Forlano R, Manousou P, Goldin R, Carling D, Hoare M, Thursz M, Mann DA, Cebola I, Posma JM, Safinia N, Oakley F, Hall Z
Publication type: Article
Publication status: Published
Journal: Metabolism: Clinical and Experimental
Year: 2025
Volume: 168
Print publication date: 01/07/2025
Online publication date: 22/03/2025
Acceptance date: 20/03/2025
Date deposited: 15/04/2025
ISSN (print): 0026-0495
ISSN (electronic): 1532-8600
Publisher: W.B. Saunders
URL: https://doi.org/10.1016/j.metabol.2025.156237
DOI: 10.1016/j.metabol.2025.156237
Data Access Statement: Mass spectrometry data is available on MassIVE database (MSV000093530). RNA sequencing data have been deposited in the European Nucleotide Archive (ENA) at EMBL-EBI (PRJEB81328).
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