Liver Tissue and Plasma Ceramide Variations in Metabolic Dysfunction‐Associated Steatotic Liver Disease Based on the Number of Ceramide Carbon Atoms

ABSTRACT Ceramides play a complex role in metabolic dysfunction‐associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction‐associated steatohepatitis (MASH). Research shows that the plasma composition of ceramides differs among patients with MASLD and MASH, albeit with inconsistent results. In this study, an untargeted lipidomic analysis was performed on liver tissue and plasma simultaneously obtained from 72 participants at the time of histology. Ceramides were compared among patients with normal histology, MASLD without MASH, and MASH with and without advanced fibrosis in the liver tissue and plasma. Data analysis found a relative reduction in quantitation was observed for ceramides with 44–47 carbon atoms, whereas other ceramide species with ≤43 and ≥58 carbon atoms increased with progressive MASLD stages. Ceramides with ≥58 carbon atoms were significantly upregulated in patients with MASLD compared with controls and in patients with MASH compared with those without MASH. This was also correlated with the severity of steatosis and ballooning in liver histology. Specific ceramide species were also positively (e.g., ceramides 64:9;3O and 62:5;3O ( r = 0.3–0.6)) or negatively (ceramide 46:5;3O ( r = –0.5)) associated with the severity of histological features ( p < 0.001). Plasma ceramide analysis showed similar trends but had no consistent pattern as observed in liver tissue. The findings suggest that the changes observed in liver tissue ceramide composition at different MASLD stages were not uniform. They differ based on the number of carbon atoms present, indicating the possibility that more than one metabolic pathway regulates ceramides in MASLD. Intervention to regulate specific ceramides can improve disease severity. Practical Application : Ceramides are sphingolipids that play an important role in the pathophysiology of MASLD and its progression to MASH. A disparity between plasma and liver tissue ceramide levels at different stages of MASLD is seen. The effects of MASLD are not uniform for all species of ceramides. Compared with other ceramides, very long‐chain ceramides show different patterns with MASLD progression. Intervention to modify specific ceramides (or groups) expression could benefit the management of MASLD and its progression.