Extracellular Vesicles <scp>miRNome</scp> Profiling Reveals <scp>miRNAs</scp> Engagement in Dysfunctional Lipid Metabolism, Chronic Inflammation and Liver Damage in Subjects With Metabolic Dysfunction‐Associated Steatotic Liver Disease
Gian Paolo Caviglia, Elisabetta Casalone, Chiara Rosso, Serena Aneli, Alessandra Allione, Fabrizia Carli, Cristina Grange, Angelo Armandi, Chiara Catalano, Giovanni Birolo, Beatrice Foglia, Davide Giuseppe Ribaldone, Amalia Gastaldelli, Giuseppe Matullo, Elisabetta Bugianesi
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: ]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.