%0 Journal Article
%A Infante‐Menéndez, Jorge 
%A López‐Pastor, Andrea R. 
%A González‐Illanes, Tamara 
%A González‐López, Paula 
%A Huertas‐Lárez, Raquel 
%A Rey, Esther 
%A González‐Rodríguez, Águeda
%A García‐Monzón, Carmelo
%A Patil, Nikita P.
%A Vega De Céniga, Melina 
%A Baker, Aaron B.
%A Gómez Hernández, María De La Almudena
%A Escribano Illanes, Óscar
%T Increased let‐7d‐5p in non‐alcoholic fatty liver promotes insulin resistance and is a potential blood biomarker for diagnosis
%D 2023
%@ 1478-3223
%@ 1478-3231
%U https://hdl.handle.net/20.500.14352/92257
%X 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.
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