Plasma ceramides decreased in Gilbert's syndrome associated with healthy blood lipid phenotypes: A cross-sectional study

BACKGROUND: Sphingolipids play an important role in the development of multiple metabolic disease. However, no study explored the impact of bilirubin on sphingolipid metabolism in human. This study aims to investigate the plasma sphingolipid profiles and their association with blood lipids in mild hyperbilirubinemia (Gilbert's syndrome; GS) individuals. METHODS: This cross-sectional study enrolled 224 participants including 112 individuals with GS and 112 age- and gender-matched healthy controls. Liquid chromatography-mass spectrometry was employed to quantify 53 plasma sphingolipid metabolites in a subset of 55 GS and 55 age- and gender-matched healthy controls. OPLS-DA model was constructed using SIMCA 14.1 software to identify distinct plasma sphingolipid metabolites between two groups. RESULTS: The median age of 224 subjects was 35 years, with males comprising 29.5%. The GS group exhibited higher levels of total bilirubin and high-density lipoprotein cholesterol, along with lower levels of triglycerides (all P < 0.05). Analysis of plasma sphingolipid revealed significant differences in 14 sphingolipids between two groups. Compared to the healthy control group, the GS group had lower levels of Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/25:0), Cer(d18:1/26:0), Cer(d18:2/16:0), CerP(d18:1/22:0), HexCer(d18:1/22:0), HexCer(d18:1/24:1), HexCer(d18:1/24:0), LacCer(d18:1/16:0), as well as higher levels of CerP(d18:1/12:0), LacCer(d18:1/24:0), sphingosine-1-phosphate, and sphinganine (all P < 0.05). Correlation analysis of 110 subjects indicated that Cer(d18:1/25:0), Cer(d18:1/26:0), Cer(d18:2/16:0), CerP(d18:1/22:0), HexCer(d18:1/22:0), HexCer(d18:1/24:0) were positively correlated with total cholesterol. Additionally, sphinganine was positively correlated with high-density lipoprotein cholesterol and sphingosine 1-phosphate was negatively correlated with triglycerides (all P < 0.05). CONCLUSION: This study demonstrated that plasma ceramide levels decreased in Gilbert's syndrome, which correlates with a favorable blood lipid profile.