{"doi":"10.1111/liv.15581","title":"Increased let‐7d‐5p in non‐alcoholic fatty liver promotes insulin resistance and is a potential blood biomarker for diagnosis","abstract":"BACKGROUND AND AIMS: The molecular mechanisms driving non-alcoholic fatty liver disease (NAFLD) are poorly understood; however, microRNAs might play a key role in these processes. We hypothesize that let-7d-5p could contribute to the pathophysiology of NAFLD and serve as a potential diagnostic biomarker. METHODS: We evaluated let-7d-5p levels and its targets in liver biopsies from a cross-sectional study including patients with NAFLD and healthy donors, and from a mouse model of NAFLD. Moreover, the induction of let-7d-5p expression by fatty acids was evaluated in vitro. Further, we overexpressed let-7d-5p in vitro to corroborate the results observed in vivo. Circulating let-7d-5p and its potential as a NAFLD biomarker was determined in isolated extracellular vesicles from human plasma by RT-qPCR. RESULTS: Our results demonstrate that hepatic let-7d-5p was significantly up-regulated in patients with steatosis, and this increase correlated with obesity and a decreased expression of AKT serine/threonine kinase (AKT), insulin-like growth factor 1 (IGF1), IGF-I receptor (IGF1R) and insulin receptor (INSR). These alterations were corroborated in a NAFLD mouse model. In vitro, fatty acids increased let-7d-5p expression, and its overexpression decreased AKT, IGF-IR and IR protein expression. Furthermore, let-7d-5p hindered AKT phosphorylation in vitro after insulin stimulation. Finally, circulating let-7d-5p significantly decreased in steatosis patients and receiver operating characteristic (ROC) analyses confirmed its utility as a diagnostic biomarker. CONCLUSIONS: Our results highlight the emerging role of let-7d-5p as a potential therapeutic target for NAFLD since its overexpression impairs hepatic insulin signalling, and also, as a novel non-invasive biomarker for NAFLD diagnosis.","journal":"Liver International","year":2023,"id":344224,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9662,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1082605,"name":"Andrea R. López‐Pastor","orcid":"0000-0002-0054-3828","position":1,"is_corresponding":false},{"id":1082606,"name":"Tamara González‐Illanes","orcid":"0000-0001-7351-5599","position":2,"is_corresponding":false},{"id":1082607,"name":"Paula González‐López","orcid":"0000-0001-5848-0172","position":3,"is_corresponding":false},{"id":1082608,"name":"Raquel Huertas‐Lárez","orcid":"0000-0001-7975-6481","position":4,"is_corresponding":false},{"id":1082609,"name":"Esther Rey","orcid":"0000-0002-8732-8994","position":5,"is_corresponding":false},{"id":1082610,"name":"Águeda González‐Rodríguez","orcid":"0000-0001-6428-6210","position":6,"is_corresponding":false},{"id":259963,"name":"Carmelo García‐Monzón","orcid":"0000-0002-2118-8706","position":7,"is_corresponding":false},{"id":687685,"name":"Nikita Patil","orcid":"0000-0002-1511-8031","position":8,"is_corresponding":false},{"id":1083118,"name":"Melina Vega de Céniga","orcid":null,"position":9,"is_corresponding":false},{"id":445646,"name":"Aaron B. Baker","orcid":"0000-0002-7991-0183","position":10,"is_corresponding":false},{"id":993373,"name":"Almudena Gómez‐Hernández","orcid":"0000-0002-2742-4298","position":11,"is_corresponding":false},{"id":1082611,"name":"Óscar Escribano","orcid":"0000-0002-8249-1645","position":12,"is_corresponding":false},{"id":1082604,"name":"Jorge Infante‐Menéndez","orcid":"0000-0003-0303-6538","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-19T01:11:30.951510Z","pmid":"37057737","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}