Background & AimsAlterations in the glycosylation of blood proteins affect protein functionality and have been linked to various diseases. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a silent disease, of which progression to advanced disease stages including metabolic dysfunction-associated steatohepatitis (MASH), fibrosis and cirrhosis often goes unnoticed. As current non-invasive diagnostic tests lack specificity, the purpose of this work was to study total blood protein N-glycosylation in individuals with MASLD and various degrees of fibrosis as compared to healthy controls.MethodsIn two independent cross-sectional cohort studies, blood N-glycosylation analysis was performed by mass spectrometry on released glycans of overall 132 MASLD patients and 99 age- and sex-matched healthy controls. Relationships between glycosylation traits and the disease spectrum of MASLD including fibrotic MASLD were investigated in comparison to healthy controls. Furthermore, publicly available transcriptomics datasets were used to explore glycosyltransferase expression in patients with MASLD.ResultsGlobally lower α2,3-sialylation distinguished MASLD from healthy controls (OR [CI]=0.36; [0.18-0.67]; p-value=0.019, and 0.11 [0.04-0.24]; p-value<0.000001), as well as non-fibrotic MASLD from its fibrotic counterparts (OR: 0.13 [0.06-0.26]; p-value<0.0001), but showed no association with steatohepatitis activity. Hepatic ST3GAL6, a sialyltransferase responsible for N-glycan α2,3-sialylation, negatively associated with fibrosis progression, similar to the observed glycomic signature. Both glycomic and transcriptomic signatures were replicated in independent cohorts.ConclusionsFibrotic MASLD is characterized by a global decrease of blood protein α2,3-sialylation and according decrease in hepatic α2,3-sialyltransferase expression, associating with disease progression. These findings suggest alterations in the N-glycan biosynthetic pathway and are potentially useful in the early diagnosis of fibrosis in MASLD.
