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Sphingolipids Are Depleted in Alcohol-Related Liver Fibrosis
Maja Thiele1, Tommi Suvitaival2, Kajetan Trošt3
1Center 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.
Gastroenterology
|February 27, 2023
Summary
Alcohol-related liver disease causes progressive depletion of sphingolipids in the liver and blood. Reduced sphingomyelin levels are linked to fibrosis and predict future liver events in alcohol-related liver disease (ALD).
Area of Science:
- Biochemistry
- Hepatology
- Metabolomics
Background:
- Alcohol consumption significantly impacts hepatic lipid metabolism.
- The precise role of lipid dysfunction in alcohol-related liver disease (ALD) remains incompletely understood.
- Early-stage ALD requires detailed characterization of liver and plasma lipid profiles.
Purpose of the Study:
- To comprehensively analyze the liver and plasma lipidomes in patients with early alcohol-related liver disease (ALD).
- To correlate lipid profiles with histological features of liver damage, including fibrosis, inflammation, and steatosis.
- To investigate the predictive value of specific lipids for liver-related events and their causal relationship with alcohol consumption.
Main Methods:
- Mass spectrometry-based lipidomics was performed on paired liver and plasma samples from 315 ALD patients and 51 healthy controls.
- Lipid levels were statistically associated with fibrosis, inflammation, and steatosis, with adjustments for confounders.
- Sphingolipid regulation was further explored using microRNA sequencing, prediction models for liver events, and Mendelian randomization studies.
Main Results:
- A total of 198 liver lipids and 236 plasma lipids from 18 classes were identified.
- Sphingolipids (sphingomyelins, ceramides) and phosphocholines were co-down-regulated in both liver and plasma, correlating negatively with fibrosis and inflammation.
- Reduced sphingomyelin levels predicted future liver-related events and were distinct in patients with ALD/nonalcoholic fatty liver disease overlap.
Conclusions:
- Alcohol-related liver fibrosis is marked by progressive depletion of liver and blood lipids, especially sphingomyelins.
- Decreased sphingomyelin levels are associated with liver fibrosis progression and predict adverse liver-related outcomes.
- Mendelian randomization supports a causal role for ALD in sphingomyelin depletion, independent of genetic susceptibility to alcohol use disorder.
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