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New microRNA biomarkers for drug-induced steatosis and their potential to predict the contribution of drugs to non-alcoholic fatty liver disease

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New microRNA biomarkers for drug-induced steatosis and their potential to predict the contribution of drugs to non-alcoholic fatty liver disease

dc.contributor.author	López-Riera, Mireia
dc.contributor.author	Conde, Isabel
dc.contributor.author	Tolosa, Laia
dc.contributor.author	Zaragoza, Angela
dc.contributor.author	Castell, José V.
dc.contributor.author	Gómez-Lechón, María J.
dc.contributor.author	Jover Atienza, Ramiro
dc.date.accessioned	2018-04-19T14:20:25Z
dc.date.available	2018-04-19T14:20:25Z
dc.date.issued	2017
dc.identifier.citation	López-Riera, Mireia Conde, Isabel Tolosa, Laia Zaragoza, Angela Castell Ripoll, José Vicente Gómez-Lechón, María J. Jover Atienza, Ramiro 2017 New microRNA biomarkers for drug-induced steatosis and their potential to predict the contribution of drugs to non-alcoholic fatty liver disease Frontiers In Pharmacology 8 3 1 12
dc.identifier.uri	http://hdl.handle.net/10550/65807
dc.description.abstract	Background and Aims: Drug-induced steatosis is a major reason for drug failure in clinical trials and post-marketing withdrawal; and therefore, predictive biomarkers are essential. These could be particularly relevant in non-alcoholic fatty liver disease (NAFLD), where most patients show features of the metabolic syndrome and are prescribed with combined chronic therapies, which can contribute to fatty liver. However, specific biomarkers to assess the contribution of drugs to NAFLD are lacking. We aimed to find microRNAs (miRNAs) responsive to steatotic drugs and to investigate if they could become circulating biomarkers for drug-induced steatosis. Methods: Human HepG2 cells were treated with drugs and changes in miRNA levels were measured by microarray and qRT-PCR. Drug-induced fat accumulation in HepG2 was analyzed by high-content screening and enzymatic methods. miRNA biomarkers were also analyzed in the sera of 44 biopsy-proven NAFLD patients and in 10 controls. Results: We found a set of 10 miRNAs [miR-22-5p, -3929, -24-2-5p, -663a, -29a-3p, -21 (5p and 3p), -27a-5p, -1260 and -202-3p] that were induced in human HepG2 cells and secreted to the culture medium upon incubation with model steatotic drugs (valproate, doxycycline, cyclosporin A and tamoxifen). Moreover, cell exposure to 17 common drugs for NAFLD patients showed that some of them (e.g., irbesartan, fenofibrate, and omeprazole) also induced these miRNAs and increased intracellular triglycerides, particularly in combinations. Finally, we found that most of these miRNAs (60%) were detected in human serum, and that NAFLD patients under fibrates showed both induction of these miRNAs and a more severe steatosis grade. Conclusion: Steatotic drugs induce a common set of hepatic miRNAs that could be used in drug screening during preclinical development. Moreover, most of these miRNAs are serum circulating biomarkers that could become useful in the diagnosis of iatrogenic steatosis.
dc.language.iso	eng
dc.relation.ispartof	Frontiers In Pharmacology, 2017, vol. 8, num. 3, p. 1-12
dc.subject	Patologia
dc.subject	Drogues
dc.subject	Farmacologia
dc.title	New microRNA biomarkers for drug-induced steatosis and their potential to predict the contribution of drugs to non-alcoholic fatty liver disease
dc.type	journal article	es_ES
dc.date.updated	2018-04-19T14:20:25Z
dc.identifier.doi	10.3389/fphar.2017.00003
dc.identifier.idgrec	125159
dc.rights.accessRights	open access	es_ES