Sphingolipids Are Depleted in Alcohol-Related Liver Fibrosis
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Background & Aims: Alcohol disturbs hepatic lipid synthesis and transport, but the role of lipid dysfunction in alcohol-related liver disease (ALD) is unclear. In this biopsy-controlled, prospective, observational study, we characterized the liver and plasma lipidomes in patients with early ALD. Methods: We performed mass spectrometry–based lipidomics of paired liver and plasma samples from 315 patients with ALD and of plasma from 51 matched healthy controls. We associated lipid levels with histologic fibrosis, inflammation, and steatosis with correction for multiple testing and adjustment for confounders. We further investigated sphingolipid regulation by means of quantitative real-time polymerase chain reaction sequencing of microRNA, prediction of liver-related events, and tested causality with Mendelian randomization. Results: We detected 198 lipids in the liver and 236 lipids in the circulation from 18 lipid classes. Most sphingolipids (sphingomyelins and ceramides) and phosphocholines were co–down-regulated in both liver and plasma, where lower abundance correlated with higher fibrosis stage. Sphingomyelins showed the most pronounced negative correlation to fibrosis, mirrored by negative correlations in both liver and plasma with hepatic inflammation. Reduced sphingomyelins predicted future liver-related events. This seemed to be characteristic of “pure ALD,” as sphingomyelin levels were higher in patients with concomitant metabolic syndrome and ALD/nonalcoholic fatty liver disease overlap. Mendelian randomization in FinnGen and UK Biobanks indicated ALD as the cause of low sphingomyelins, and alcohol use disorder did not correlate with genetic susceptibility to low sphingomyelin levels. Conclusions: Alcohol-related liver fibrosis is characterized by selective and progressive lipid depletion in liver and blood, particularly sphingomyelins, which also associates with progression to liver-related events.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Gastroenterology |
| Vol/bind | 164 |
| Udgave nummer | 7 |
| Sider (fra-til) | 1248-1260 |
| ISSN | 0016-5085 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
Funding This project received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement 668031 to the GALAXY Consortium, and from the Challenge grant NNF15OC0016692 from the Novo Nordisk Foundation to the MicrobLiver Consortium. Maja Thiele is funded by a grant from the Novo Nordisk Foundation (NNF20OC0059393).
Funding Information:
MicrobLiver Consortium: Peer Bork, Mathias Mann, Jelle Matthijnssens, Aleksander Krag, and Torben Hansen (coordinator). GALAXY consortium: Ema Anastasiadou, Manimozhiyan Arumugam, Peer Bork, Torben Hansen, Roland Henrar, Hans Israelsen, Morten Karsdal, Cristina Legido-Quigley, Hans Olav Melberg, Maja Thiele, Jonel Trebicka, and Aleksander Krag (coordinator). The authors wish to thank Louise Skovborg Just and Lise Ryborg for managing the GALAXY and MicrobLiver consortia; Angus King for language revision; Julie Hansen and the rest of the personnel at Center for Liver Research for assistance in the conduct of clinical investigations; Karsten Lauridsen and Benedicte Wilson, heads of Department for Gastroenterology and Hepatology at Odense University Hospital; the personnel and management at Odense Municipality Alcohol Rehabilitation Centre, and OPEN Patient Data Exploratory Network for data management support. Maja Thiele, MD, PhD (Investigation: Lead; Writing – original draft: Equal; Writing – review & editing: Equal). Tommi Suvitaival, DSc (Data curation: Lead; Formal analysis: Lead; Methodology: Lead; Software: Lead; Validation: Lead; Visualization: Lead; Writing – original draft: Equal; Writing – review & editing: Lead). Kajetan Trošt, PhD (Data curation: Equal; Investigation: Equal; Writing – original draft: Supporting). Min Kim, PhD (Data curation: Equal; Investigation: Equal). Andressa de Zawadzki, PhD (Data curation: Supporting; Writing – review & editing: Supporting). Maria Kjaergaard, MD (Investigation: Supporting). Ditlev Nytoft Rasmussen, MD, PhD (Data curation: Equal; Investigation: Supporting). Katrine Prier Lindvig, MD (Investigation: Supporting). Mads Israelsen, MD, PhD (Investigation: Supporting; Writing – review & editing: Supporting). Sönke Detlefsen, MD, PhD (Investigation: Supporting; Writing – review & editing: Supporting). Peter Andersen, MSc (Project administration: Lead). Helene Baek Juel, PhD (Project administration: Supporting; Writing – review & editing: Supporting). Trine Nielsen, PhD (Project administration: Supporting). Stella Georgiou, PhD (Formal analysis: Supporting). Vicky Filippa, PhD (Formal analysis: Supporting). Michael Kuhn, PhD (Formal analysis: Supporting; Resources: Equal). Suguru Nishijima, PhD (Formal analysis: Supporting; Resources: Equal; Visualization: Supporting; Writing – original draft: Supporting). Lucas Moitinho-Silva, PhD (Formal analysis: Supporting; Resources: Equal; Writing – review & editing: Supporting). Peter Rossing, MD, DMSc (Project administration: Supporting). Jonel Trebicka, MD, PhD (Funding acquisition: Equal). Ema Anastasiadou, PhD (Funding acquisition: Equal; Writing – original draft: Supporting). Peer Bork, PhD (Funding acquisition: Equal; Resources: Equal). Torben Hansen, MD, PhD (Conceptualization: Equal; Funding acquisition: Equal). Cristina Legido-Quigley, PhD (Conceptualization: Equal; Supervision: Equal; Writing – original draft: Supporting). Aleksander Krag, MD, PhD (Conceptualization: Equal; Funding acquisition: Lead; Supervision: Equal; Writing – original draft: Supporting). FundingThis project received funding from the European Union's Horizon 2020 research and innovation program under grant agreement 668031 to the GALAXY Consortium, and from the Challenge grant NNF15OC0016692 from the Novo Nordisk Foundation to the MicrobLiver Consortium. Maja Thiele is funded by a grant from the Novo Nordisk Foundation (NNF20OC0059393).
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© 2023 The Authors
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