Extracellular Vesicle-Based miRNA Profiling in Metabolic Dysfunction-Associated Steatotic Liver Disease: A Secondary Analysis of the MULTISITE Clinical Trial

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the worldwide leading cause of liver-related mortality with a prevalence of 75% among individuals with obesity and lacking screenings tools. Extracellular vesicles (EVs)-based microRNAs (miRNAs) have emerged as promising biomarkers with important roles in the pathogenesis of MASLD. This study aimed to characterize EV-based miRNA profiles in individuals with obesity and MASLD before and during weight loss intervention. Small RNA sequencing was used to profile EV-miRNAs from plasma across three groups: individuals with obesity and MASLD (n = 35), individuals with obesity without hepatic steatosis (n = 24) and lean controls without hepatic steatosis (n = 26). Further, the MASLD group underwent a personalized weight-loss intervention. The liver and MASLD-related miR-122-5p and three other miRNAs were differentially expressed in the MASLD group compared with the obesity control group at baseline. Moreover, miR-122-5p correlated with liver fat and liver enzymes (ALT, AST and GGT) at baseline, revealed solid predictability for MASLD in a combined panel (AUC = 0.8), and lastly demonstrated the highest accuracy in identifying individuals with high liver fat among all individuals with obesity. Finally, several MASLD- and hepatocellular carcinoma-related miRNAs decreased significantly following weight loss and liver fat reduction in the MASLD group.