Association of the Liver and Plasma Lipidomes with the Histological Severity Stage of Alcohol-Related Liver Disease

Novo Nordisk Foundation Challenge Symposium
Abstract

1. Theme

Fatty liver diseases: NASH, ASH and cirrhosis

2. Title of Abstract / Poster

Association of the Liver and Plasma Lipidomes with the Histological Severity
Stage of Alcohol-Related Liver Disease

3. Full author name and affiliation, names of all co-authors and their affiliations

Tommi Suvitaival1, Maja Thiele2,3+, Kajetan Trošt1,5+, Min Kim1, Andressa de Zewadzki1, Maria Kjaergaard2,3, Ditlev Nytoft Rasmussen2, Katrine Prier Lindvig2,3, Mads Israelsen2, Sönke Detlefsen3,4, Peter Andersen2, Helene Bæk Juel5, Trine Nielsen5, Stella Georgiou6, Vicky Filippa6, Michael Kuhn7, Suguru Nishijima7, Lucas Moitinho-Silva7, Peter Rossing1, Jonel Trebicka2,9,10, Ema Anastasiadou6, Peer Bork7, Torben Hansen5, Cristina Legido Quigley1,8, Aleksander Krag2,3, on behalf of the MicrobLiver and GALAXY Consortia

1: Steno Diabetes Center Copenhagen, Gentofte, Denmark
2: Center for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
3: Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
4: Department of Pathology, Odense University Hospital, Odense, Denmark
5: Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
6: Department of Genetics, Biomedical Research Foundation of Academy of Athens, Athens, Greece
7: European Molecular Biology Laboratory, Heidelberg, Germany
8 Institute of Pharmaceutical Science, School of Life Science & Medicine, King’s College London, London UK
9: Translational Hepatology, Department of Internal Medicine I, Goethe University Frankfurt, Germany
10: European Foundation for the study of Chronic Liver Failure, EFCLIF, Barcelona, Spain

4. Background

Alcohol disturbs hepatic lipid synthesis and transport, but the role of lipid dysfunction in the severity of alcohol-related liver disease (ALD) is unclear.

5. Objective

We therefore characterized the liver and plasma lipidome in a biopsy-controlled cohort of patients with early ALD.

6. Methods

We performed ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry for lipidomics of the liver and plasma from 315 patients, and of plasma from 51 healthy controls matched for age, gender and BMI. We correlated lipid levels with histological fibrosis, inflammation and steatosis, after correction for multiple testing and adjustment for age, gender, statin use, BMI, HbA1c, HOMA-IR, and ongoing drinking. Moreover, we investigated the mechanism of dysregulated sphingolipid metabolism by whole-blood transcriptomics and qPCR sequencing of miRNA.

7. Results

We detected 198 lipids in the liver and 236 lipids in the circulation from 18 lipid classes. Nearly all ceramides, sphingomyelins and lyso-phosphocholines in plasma decreased as fibrosis progressed. This was paralleled by a comparable decrease in the liver. Circulating and liver sphingomyelins were also inversely associated with hepatic inflammation. The lipidomic signature of healthy controls was only comparable to ALD patients with no fibrosis. Three circulating miRNA, highly involved in sphingomyelin metabolism, were dysregulated together with the mRNA expression of enzymes in the sphingomyelin degradation pathway. Mendelian randomization in Finnish and UK population biobanks externally validated our findings, suggesting a causal relationship between genetic disposition to ALD and low sphingolipid levels.

8. Conclusion
Liver fibrosis severity in alcohol-related liver disease is characterized by selective lipid depletion in blood and liver, indicating profound effects of progressive disease on the bioactive sphingolipids, already from early stages of fibrosis.