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Updated: May 20, 2025
A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors
Published on: June 8, 2022
Spatial lipidomics reveals sphingolipid metabolism as anti-fibrotic target in the liver
Aleksandra Gruevska1, Jack Leslie2, Elena Perpiñán3
1Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom.
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.
Insights
Dysregulated sphingolipid metabolism in the liver promotes fibrosis. Targeting these pathways, particularly sphingomyelin, shows promise for developing new anti-fibrotic therapies for steatotic liver disease.
Area of Science:
- Hepatology
- Lipid Metabolism
- Fibrosis Research
Background:
- Steatotic liver disease (SLD) is a significant driver of liver fibrosis.
- Understanding lipotoxicity and lipid metabolism is key for developing SLD therapies.
Purpose of the Study:
- To investigate the role of lipid metabolism in liver fibrosis.
- To identify specific lipid species and cellular mechanisms involved in fibrogenesis.
- To explore therapeutic strategies targeting lipid metabolism.
Main Methods:
- Analysis of liver tissue from SLD patients and mouse models.
- Integration of bulk/spatial lipidomics, transcriptomics, and imaging mass cytometry (IMC).
- Pharmacological inhibition of sphingolipid metabolism in hepatic stellate cells (HSCs) and human precision cut liver slices (hPCLSs).
Main Results:
- Increased glycosphingolipids, ether lipids, and saturated phosphatidylcholines in fibrotic liver tissue.
- Enrichment of sphingomyelin (SM) 34:1 and dysregulated sphingolipid synthesis gene expression in fibrotic regions.
- Spatial correlation between sphingolipids and myofibroblasts; inhibition of sphingolipid metabolism demonstrated anti-fibrotic effects.
Conclusions:
- Spatial multi-omics reveals cell type-specific fibrogenesis mechanisms involving sphingolipid metabolism.
- Sphingolipid metabolic pathways are modifiable targets for anti-fibrotic therapy in SLD.
