A microRNA signature for valproate-induced steatosis in human hepatocytes and its application to predict fatty liver in paediatric epileptic patients on valproate therapy

• Published in: Toxicology (Amsterdam) 2024-12, Vol.509, p.153974, Article 153974
• Main Authors: Soluyanova, Polina, del Pozo, Marta, Moro-Castaño, Erika, Marco-Hernández, Ana V., Castell, José V., Jover, Ramiro
• Format: Article
• Language: English
• Subjects: Adolescent; Anticonvulsants - adverse effects; Anticonvulsants - toxicity; Biomarkers - blood; Biomarkers - metabolism; Cells, Cultured; Child; Child, Preschool; Diagnosis biomarker; Epilepsy - drug therapy; Epilepsy - genetics; Epileptic patient; Fatty Liver - chemically induced; Fatty Liver - genetics; Female; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatotoxicity; Humans; Idiosyncratic drug-induced liver injury; Liquid-biopsy; Liver steatosis; Male; MicroRNA; MicroRNAs - blood; MicroRNAs - genetics; Triglycerides - blood; Valproic Acid - adverse effects; Valproic Acid - toxicity; Valproic acid / Valproate
• ISSN: 0300-483X; 1879-3185; 1879-3185
• DOI: 10.1016/j.tox.2024.153974

Valproate (VPA) has been the first-line, most frequently prescribed antiepileptic drug in children over the past 50 years. VPA causes, idiosyncratic hepatotoxicity in some patients, who often presents with hepatic steatosis. Experimental studies also support that VPA has high potential to induce steatosis. However, there is an apparent lack of significant hepatic problems in neuropediatric units, likely because iatrogenic liver steatosis lacks specific biomarkers. Thus, it is possible that a relevant number of children under VPA have asymptomatic fatty liver. 1) to demonstrate VPA-induced triglyceride (TG) accumulation in cultured human upcyte hepatocytes, 2) to identify miRNAs that are deregulated by VPA and associated with TG levels in these cells, and 3) to test these miRNAs, as potential non-invasive biomarkers, in plasma of paediatric epileptic patients on VPA, to identify those with a potential risk of liver steatosis. Human upcyte hepatocytes were exposed to subcytotoxic VPA concentrations. Hepatocytes increased intracellular TGs by 27 % and 45 % after 2 and 4 mM VPA for 24 h. The profiling of cellular miRNAs by microarray analysis after 4 mM VPA identified 43 deregulated human miRNAs (fold-change > 1.5 or < −1.5; FDR p