Sphingolipids Are Depleted in Alcohol-Related Liver Fibrosis.

Autor:	Thiele M; Center for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark., Suvitaival T; Steno Diabetes Center Copenhagen, Herlev, Denmark., Trošt K; Steno Diabetes Center Copenhagen, Herlev, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Kim M; Steno Diabetes Center Copenhagen, Herlev, Denmark., de Zawadzki A; Steno Diabetes Center Copenhagen, Herlev, Denmark., Kjaergaard M; Center for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark., Rasmussen DN; Center for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark., Lindvig KP; Center for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark., Israelsen M; Center for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark., Detlefsen S; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark; Department of Pathology, Odense University Hospital, Odense, Denmark., Andersen P; Center for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark., Juel HB; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Nielsen T; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Georgiou S; Department of Genetics, Biomedical Research Foundation of Academy of Athens, Athens, Greece., Filippa V; Department of Genetics, Biomedical Research Foundation of Academy of Athens, Athens, Greece., Kuhn M; European Molecular Biology Laboratory, Heidelberg, Germany., Nishijima S; European Molecular Biology Laboratory, Heidelberg, Germany., Moitinho-Silva L; European Molecular Biology Laboratory, Heidelberg, Germany., Rossing P; Steno Diabetes Center Copenhagen, Herlev, Denmark., Trebicka J; Center for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark; Medizinische Klinik B, Universitätsklinikum Münster, Münster University, Münster, Germany; European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain., Anastasiadou E; Department of Genetics, Biomedical Research Foundation of Academy of Athens, Athens, Greece., Bork P; European Molecular Biology Laboratory, Heidelberg, Germany., Hansen T; Department of Pathology, Odense University Hospital, Odense, Denmark., Legido-Quigley C; Steno Diabetes Center Copenhagen, Herlev, Denmark; Institute of Pharmaceutical Science, School of Life Science and Medicine, King's College London, London, United Kingdom. Electronic address: cristina.legido.quigley@regionh.dk., Krag A; Center for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark. Electronic address: Aleksander.Krag@rsyd.dk.
Jazyk:	angličtina
Zdroj:	Gastroenterology [Gastroenterology] 2023 Jun; Vol. 164 (7), pp. 1248-1260. Date of Electronic Publication: 2023 Feb 26.
DOI:	10.1053/j.gastro.2023.02.023
Abstrakt:	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. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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