Sphingolipids Are Depleted in Alcohol-Related Liver Fibrosis.

Humans Sphingolipids / metabolism Sphingomyelins / metabolism Prospective Studies Liver Cirrhosis / genetics Liver / pathology Ethanol / metabolism Non-alcoholic Fatty Liver Disease / pathology Fibrosis Inflammation / metabolism

Alcoholic Liver Disease Fatty Liver Fibrosis Metabolomics

Journal

Gastroenterology

ISSN: 1528-0012

Titre abrégé: Gastroenterology

Pays: United States

ID NLM: 0374630

Informations de publication

Date de publication:
06 2023

Historique:

received: 27 04 2022

revised: 30 01 2023

accepted: 08 02 2023

medline: 23 5 2023

pubmed: 28 2 2023

entrez: 27 2 2023

Statut: ppublish

Résumé

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. 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. 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. 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.

Sections du résumé

BACKGROUND & AIMS

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.

Identifiants

DOI: 10.1053/j.gastro.2023.02.023 PMID: 36849086

pubmed: 36849086

pii: S0016-5085(23)00162-2

doi: 10.1053/j.gastro.2023.02.023

pii:

doi:

Substances chimiques

Sphingolipids 0

Sphingomyelins 0

Ethanol 3K9958V90M

Types de publication

Observational Study Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1248-1260

Investigateurs

Peer Bork (P)

Mathias Mann (M)

Jelle Matthijnssens (J)

Aleksander Krag (A)

Torben Hansen (T)

Ema Anastasiadou (E)

Manimozhiyan Arumugam (M)

Peer Bork (P)

Torben Hansen (T)

Roland Henrar (R)

Hans Israelsen (H)

Morten Karsdal (M)

Cristina Legido-Quigley (C)

Hans Olav Melberg (HO)

Maja Thiele (M)

Jonel Trebicka (J)