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
Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Turin, Italy.
Unit of Genomic, Department of Medical Sciences, University of Turin, Turin, Italy.
Aliment Pharmacol Ther. 2025 Jul;62(1):22-32. doi: 10.1111/apt.70150. Epub 2025 Apr 10.
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).
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-H]glucose and [H]glycerol) to assess glucose and lipid fluxes and insulin resistance (IR) in the adipose tissue.
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.
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.
微小RNA（miRNA）是参与基因表达转录后调控的短链非编码寡核苷酸。我们研究了循环细胞外囊泡（EV）的miRNome图谱与代谢紊乱、循环和肝脏促炎细胞因子以及代谢功能障碍相关脂肪性肝病（MASLD）组织学谱中的肝损伤之间的关联。
通过二代测序（NextSeq550，Illumina公司）测定228例经活检证实的MASLD患者的EV miRNA表达。对54例患者亚组进行体内代谢研究，通过示踪剂输注（[6,6-H]葡萄糖和[H]甘油）评估脂肪组织中的葡萄糖和脂质通量以及胰岛素抵抗（IR）。
根据脂肪性肝炎的诊断和显著纤维化（F≥2）的存在，七种miRNA（miR-27b-3p、miR-30a-5p、miR-122-5p、miR-375-3p、miR-103a-3p、let-7d-5p和let-7f-5p）表达存在差异，从而标记出“高危MASH”患者。在代谢研究中，上述miRNA与脂质代谢关联最强：miR-122-5p和miR-375-3p水平与循环游离脂肪酸（FFA）和脂肪组织（AT）-IR直接相关，而let-7d-5p和let-7f-5p与脂解、FFA呈负相关，并根据AT-IR严重程度逐渐降低。此外，let-7d-5p和let-7f-5p与促炎细胞因子的循环和肝脏表达呈负相关，促炎细胞因子随着AT-IR程度的增加而升高。
我们的结果表明，miR-122-5p、miR-375-3p和let-7家族在调节“高危MASH”患者的脂质紊乱和炎症途径方面存在相互联系，为进一步研究其潜在治疗价值奠定了基础。
