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oai:docta.ucm.es:20.500.14352/922572024-05-14T14:19:02Zcom_20.500.14352_14col_20.500.14352_15

Increased let‐7d‐5p in non‐alcoholic fatty liver promotes insulin resistance and is a potential blood biomarker for diagnosis Infante‐Menéndez, Jorge López‐Pastor, Andrea R. González‐Illanes, Tamara González‐López, Paula Huertas‐Lárez, Raquel Rey, Esther González‐Rodríguez, Águeda García‐Monzón, Carmelo Patil, Nikita P. Vega De Céniga, Melina Baker, Aaron B. Gómez Hernández, María De La Almudena Escribano Illanes, Óscar 577.2 612.015 Biología molecular (Farmacia) Bioquímica (Farmacia) 2403 Bioquímica 2302.21 Biología Molecular 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 pathophysiol-ogy 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 corrobo-rated 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, cir-culating let-7d- 5p significantly decreased in steatosis patients and receiver operating characteristic (ROC) analyses confirmed its utility as a diagnostic biomarker. Ministerio de Ciencia, Innovación y Universidades Santander-UCM UCM Instituto de Salud Carlos III Fondo Europeo para el Desarrollo Regional (FEDER) American Heart Association DOD CDMRP National Institutes of Health Depto. de Bioquímica y Biología Molecular Fac. de Farmacia TRUE pub 2024-01-10T13:11:12Z 2024-01-10T13:11:12Z 2023-04-14 journal article https://hdl.handle.net/20.500.14352/92257 1478-3223 1478-3231 10.1111/liv.15581 eng info:eu-repo/grantAgreement/RTI-2018-095098-B100 info:eu-repo/grantAgreement/PID2021-123076OB-I00 info:eu-repo/grantAgreement/AENC1/22-29754 info:eu-repo/grantAgreement/PR75/18-21572 info:eu-repo/grantAgreement/PI20/00837 info:eu-repo/grantAgreement/PI19/00123 info:eu-repo/grantAgreement/17IRG33410888 info:eu-repo/grantAgreement/W81XWH-16-1-0580 info:eu-repo/grantAgreement/W81XWH-16-1-0582 info:eu-repo/grantAgreement/R21EB023551-01 info:eu-repo/grantAgreement/1R21EB024147-01A1 info:eu-repo/grantAgreement/1R01HL141761-01 Infante-Menéndez J, López-Pastor AR, González-Illanes T, González-López P, Huertas-Lárez R, Rey E, González-Rodríguez Á, García-Monzón C, Patil NP, Vega de Céniga M, Baker AB, Gómez-Hernández A, Escribano O. Increased let-7d-5p in non-alcoholic fatty liver promotes insulin resistance and is a potential blood biomarker for diagnosis. Liver Int. 2023 Aug;43(8):1714-1728. doi: 10.1111/liv.15581. Epub 2023 Apr 14. PMID: 37057737; PMCID: PMC10523911. Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ open access application/pdf Wiley