Extracellular Vesicles miRNome Profiling Reveals miRNAs Engagement in Dysfunctional Lipid Metabolism, Chronic Inflammation and Liver Damage in Subjects With Metabolic Dysfunction‐Associated Steatotic Liver Disease

• Published in: Alimentary pharmacology & therapeutics Vol. 62; no. 1; pp. 22 - 32
• Main Authors: Caviglia, Gian Paolo, Casalone, Elisabetta, Rosso, Chiara, Aneli, Serena, Allione, Alessandra, Carli, Fabrizia, Grange, Cristina, Armandi, Angelo, Catalano, Chiara, Birolo, Giovanni, Foglia, Beatrice, Ribaldone, Davide Giuseppe, Gastaldelli, Amalia, Matullo, Giuseppe, Bugianesi, Elisabetta
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.07.2025; John Wiley and Sons Inc
• Subjects: Adipose tissue; Adult; Aged; Biopsy; Body fat; Cytokines; Ev Mirnas and Masld; Extracellular vesicles; Extracellular Vesicles - genetics; Extracellular Vesicles - metabolism; Fatty Liver - genetics; Fatty Liver - metabolism; Female; FFA; Fibrosis; Gene expression; Gene Expression Profiling; Gene regulation; Humans; Inflammation; Inflammation - genetics; Inflammation - metabolism; Insulin Resistance; Lipid metabolism; Lipid Metabolism - genetics; Lipids; Lipolysis; Liver - metabolism; Liver - pathology; Liver diseases; Male; MASLD; Metabolism; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; miRNA; Oligonucleotides; Original; steatohepatitis; FFA; steatohepatitis; miRNA; MASLD; insulin resistance
• ISSN: 0269-2813; 1365-2036; 1365-2036
• DOI: 10.1111/apt.70150

ABSTRACT Background and Aims MicroRNAs (miRNAs) are short non‐coding oligonucleotides involved in the post‐transcriptional regulation of gene expression. We investigated the association between the miRNome profile of circulating extracellular vesicles (EVs) and metabolic derangements, circulating and hepatic pro‐inflammatory cytokines, and liver damage across the histological spectrum of metabolic dysfunction‐associated steatotic liver disease (MASLD). Methods EV miRNAs expression was determined by NGS (NextSeq550, Illumina Inc) in 228 biopsy‐proven MASLD patients. In vivo metabolic studies were performed in a subgroup of 54 patients by tracer infusion ([6,6‐2H2]glucose and [2H5]glycerol) to assess glucose and lipid fluxes and insulin resistance (IR) in the adipose tissue. Results Seven miRNAs (miR‐27b‐3p, miR‐30a‐5p, miR‐122‐5p, miR‐375‐3p, miR‐103a‐3p, let‐7d‐5p, and let‐7f‐5p) were differentially expressed according to the diagnosis of steatohepatitis and the presence of significant fibrosis (F ≥ 2), thus marking subjects with ‘at‐risk MASH’. In the metabolic studies, the above‐reported miRNAs had the strongest associations with lipid metabolism: miR‐122‐5p and miR‐375‐3p levels directly correlated with circulating free fatty acids (FFAs) and adipose tissue (AT)‐IR, while let‐7d‐5p and let‐7f‐5p inversely correlated with lipolysis, FFAs, and progressively decreased according to AT‐IR severity. In addition, let‐7d‐5p and let‐7f‐5p inversely correlated with the circulating and hepatic expression of pro‐inflammatory cytokines, which increased by increasing degrees of AT‐IR. Conclusions Our results suggest an intertwined connection between miR‐122‐5p, miR‐375‐3p, and the let‐7 family in modulating lipid derangements and inflammatory pathways in patients with ‘at‐risk MASH’, paving the basis for further studies aiming at investigating their potential therapeutic value. This study explores the association between the miRNome profile of circulating extracellular vesicles and metabolic dysfunction, liver inflammation, and damage in patients with metabolic MASLD, identifying key miRNAs (miR‐122‐5p, miR‐375‐3p, let‐7d‐5p, and let‐7f‐5p) that modulate lipid metabolism and inflammatory pathways in ‘at‐risk MASH’ patients.