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

Abstract Background and aims Alcohol disturbs hepatic lipid synthesis and transport, but the role of lipid dysfunction in the severity of alcohol-related liver disease (ALD) is unclear. We therefore characterised the liver and plasma lipidome in a biopsy-controlled cohort of patients with early ALD. 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. 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. Conclusions 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. Visual Abstract Highlights The lipidome in the liver and circulation in alcohol-related liver disease (ALD) Sphingolipid, phospholipid and triacylglycerol levels were lowered in fibrosis Expression and regulation of genes in the sphingolipid pathway were affected ALD has a causal link to lowered sphingomyelin levels in blood Lay summary Alcohol causes a dysfunctional fat metabolism in the liver. In this study, we detected 198 different types of lipids in the liver and 236 in the blood stream of patients with different severity of alcohol-related liver disease. We found that patients with more severe scarring (fibrosis) of the liver, and more severe liver inflammation, had lower levels of sphingolipids both in the circulation and the liver. Sphingolipids regulate cell survival and inflammation, so they may be involved in the mechanism of progressive alcohol-related liver disease.