Liver Metabolomic Profiling Reveals Distinct Signatures Between Steatosis and Metabolic Dysfunction-Associated...

Area of Science:

• Hepatology
• Metabolomics
• Obesity Medicine

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver condition linked to obesity and metabolic syndrome.
• The progression from MASLD to metabolic dysfunction-associated steatohepatitis (MASH) and its underlying metabolic drivers remain incompletely understood.

Purpose of the Study:

• To investigate the distinct liver metabolic profiles associated with MASLD and MASH.
• To identify specific metabolites and pathways linked to the progression of MASH in patients with severe obesity.

Main Methods:

• Non-targeted metabolomics analysis of liver samples from Finnish and French cohorts of patients with obesity and MASLD/MASH.
• Integration of liver metabolomics with RNA sequencing data to explore metabolic differences and pathway associations.
• Validation of identified metabolites in an independent patient cohort.

Main Results:

• Significant differences in 45 liver metabolites were observed between patients with steatosis and those with MASH.
• Novel MASH-associated metabolites identified include n-acetylneuraminate, pentose acid, UDP-galactose, gamma/beta-tocopherol, and guanidinosuccinate.
• Elevated metabolites in MASH were linked to inflammatory pathways, while decreased metabolites were associated with fatty acid degradation and amino acid metabolism.

Conclusions:

• The transition from simple steatosis to MASH is characterized by specific alterations in liver metabolites.
• These metabolic changes are associated with distinct systemic metabolic traits and highlight pathways involved in MASH progression.
• Metabolomic profiling offers insights into the mechanisms driving MASH development and progression.