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

Increased let‐7d‐5p in non‐alcoholic fatty liver promotes insulin resistance and is a potential blood biomarker for diagnosis

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Infante- Menéndez et al Liver Int 2023.pdf (27.77 MB)

Official URL

https://doi.org/10.1111/liv.15581

Publication date

2023

Authors

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

Publisher

Wiley

Citations

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URI

https://hdl.handle.net/20.500.14352/92257

Citation

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.

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 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.