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We hypothesize that let\u20107d\u20105p could contribute to the pathophysiology of NAFLD and serve as a potential diagnostic biomarker.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We evaluated let\u20107d\u20105p levels and its targets in liver biopsies from a cross\u2010sectional study including patients with NAFLD and healthy donors, and from a mouse model of NAFLD. Moreover, the induction of let\u20107d\u20105p expression by fatty acids was evaluated in vitro. Further, we overexpressed let\u20107d\u20105p in vitro to corroborate the results observed in vivo. Circulating let\u20107d\u20105p and its potential as a NAFLD biomarker was determined in isolated extracellular vesicles from human plasma by RT\u2010qPCR.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our results demonstrate that hepatic let\u20107d\u20105p was significantly up\u2010regulated in patients with steatosis, and this increase correlated with obesity and a decreased expression of AKT serine\/threonine kinase (<jats:italic>AKT<\/jats:italic>), insulin\u2010like growth factor 1 (<jats:italic>IGF1<\/jats:italic>), IGF\u2010I receptor (<jats:italic>IGF1R<\/jats:italic>) and insulin receptor (<jats:italic>INSR<\/jats:italic>). These alterations were corroborated in a NAFLD mouse model. In vitro, fatty acids increased let\u20107d\u20105p expression, and its overexpression decreased AKT, IGF\u2010IR and IR protein expression. Furthermore, let\u20107d\u20105p hindered AKT phosphorylation in vitro after insulin stimulation. Finally, circulating let\u20107d\u20105p significantly decreased in steatosis patients and receiver operating characteristic (ROC) analyses confirmed its utility as a diagnostic biomarker.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results highlight the emerging role of let\u20107d\u20105p as a potential therapeutic target for NAFLD since its overexpression impairs hepatic insulin signalling, and also, as a novel non\u2010invasive biomarker for NAFLD diagnosis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15581","type":"journal-article","created":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T10:34:49Z","timestamp":1681468489000},"page":"1714-1728","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Increased let\u20107d\u20105p in non\u2010alcoholic fatty liver promotes insulin resistance and is a potential blood biomarker for diagnosis"],"prefix":"10.1111","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0303-6538","authenticated-orcid":false,"given":"Jorge","family":"Infante\u2010Men\u00e9ndez","sequence":"first","affiliation":[{"name":"Laboratory of Hepatic and Cardiovascular Diseases, Biochemistry and Molecular Biology Department, School of Pharmacy Complutense University of Madrid  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0054-3828","authenticated-orcid":false,"given":"Andrea R.","family":"L\u00f3pez\u2010Pastor","sequence":"additional","affiliation":[{"name":"Laboratory of Hepatic and Cardiovascular Diseases, Biochemistry and Molecular Biology Department, School of Pharmacy Complutense University of Madrid  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Gonz\u00e1lez\u2010Illanes","sequence":"additional","affiliation":[{"name":"Laboratory of Hepatic and Cardiovascular 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