Sphingolipids Are Depleted in Alcohol-Related Liver Fibrosis
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Sphingolipids Are Depleted in Alcohol-Related Liver Fibrosis. / Thiele, Maja; Suvitaival, Tommi; Trošt, Kajetan; Kim, Min; de Zawadzki, Andressa; Kjaergaard, Maria; Rasmussen, Ditlev Nytoft; Lindvig, Katrine Prier; Israelsen, Mads; Detlefsen, Sönke; Andersen, Peter; Juel, Helene Bæk; Nielsen, Trine; Georgiou, Stella; Filippa, Vicky; Kuhn, Michael; Nishijima, Suguru; Moitinho-Silva, Lucas; Rossing, Peter; Trebicka, Jonel; Anastasiadou, Ema; Bork, Peer; Hansen, Torben; Legido-Quigley, Cristina; Krag, Aleksander; Mann, Mathias; Matthijnssens, Jelle; Arumugam, Manimozhiyan; Henrar, Roland; Israelsen, Hans; Karsdal, Morten; Melberg, Hans Olav; MicrobLiver Consortium; GALAXY Consortium.
In: Gastroenterology, Vol. 164, No. 7, 2023, p. 1248-1260.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Sphingolipids Are Depleted in Alcohol-Related Liver Fibrosis
AU - Thiele, Maja
AU - Suvitaival, Tommi
AU - Trošt, Kajetan
AU - Kim, Min
AU - de Zawadzki, Andressa
AU - Kjaergaard, Maria
AU - Rasmussen, Ditlev Nytoft
AU - Lindvig, Katrine Prier
AU - Israelsen, Mads
AU - Detlefsen, Sönke
AU - Andersen, Peter
AU - Juel, Helene Bæk
AU - Nielsen, Trine
AU - Georgiou, Stella
AU - Filippa, Vicky
AU - Kuhn, Michael
AU - Nishijima, Suguru
AU - Moitinho-Silva, Lucas
AU - Rossing, Peter
AU - Trebicka, Jonel
AU - Anastasiadou, Ema
AU - Bork, Peer
AU - Hansen, Torben
AU - Legido-Quigley, Cristina
AU - Krag, Aleksander
AU - Mann, Mathias
AU - Matthijnssens, Jelle
AU - Arumugam, Manimozhiyan
AU - Henrar, Roland
AU - Israelsen, Hans
AU - Karsdal, Morten
AU - Melberg, Hans Olav
AU - MicrobLiver Consortium
AU - GALAXY Consortium
N1 - Publisher Copyright: © 2023 The Authors
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - Alcoholic Liver Disease
KW - Fatty Liver
KW - Fibrosis
KW - Metabolomics
U2 - 10.1053/j.gastro.2023.02.023
DO - 10.1053/j.gastro.2023.02.023
M3 - Journal article
C2 - 36849086
AN - SCOPUS:85153046448
VL - 164
SP - 1248
EP - 1260
JO - Gastroenterology
JF - Gastroenterology
SN - 0016-5085
IS - 7
ER -
ID: 345644907