The serum acylcarnitines profile in epileptic children treated with valproic acid and the protective roles of peroxisome proliferator-activated receptor a activation in valproic acid-induced liver injury

Valproic acid (VPA) is widely used as a major drug in the treatment of epilepsy. Despite the undisputed pharmacological importance and effectiveness of VPA, its potential hepatotoxicity is still a major concern. Being a simple fatty acid, the hepatotoxicity induced by VPA has long been considered to be due primarily to its interference with fatty acid beta-oxidation (beta-FAO). The aim of this study was to investigate the biomarkers for VPA-induced abnormal liver function in epileptic children and to determine potential mechanisms of its liver injury. Targeted metabolomics analysis of acylcarnitines (ACs) was performed in children's serum. Metabolomic analysis revealed that VPA -induced abnormal liver function resulted in the accumulation of serum long-chain acylcarnitines (LCACs), and the reduced expression of beta-FAO relevant genes (Carnitine palmitoyltrans-ferase (CPT)1, CPT2 and Long-chain acyl-CoA dehydrogenase (LCAD)), indicating the disruption of beta-FAO. As direct peroxisome proliferator-activated receptor a (PPAR alpha)- regulated genes, CPT1A, CPT2 and LCAD were up-regulated after treatment with PPAR alpha agonist, fenofibrate (Feno), indicating the improvement of beta-FAO. Feno significantly ameliorated the accumulation of various lipids in the plasma of VPA-induced hepatotoxic mice by activating PPAR alpha, significantly reduced the plasma ACs concentration, and attenuated VPA-induced hepatic steatosis. Enhanced oxidative stress and induced by VPA exposure were significantly recovered using Feno treatment. In conclusion, this study indicates VPA-induced beta-FAO disruption might lead to liver injury, and a significant Feno protective effect against VPA -induced hepatotoxicity through reversing fatty acid metabolism.

Automated summary

Valproic acid (VPA) is widely used in the treatment of epilepsy, but its potential hepatotoxicity is a major concern. This study aimed to investigate the biomarkers and mechanisms of VPA-induced liver injury in epileptic children. Metabolomic analysis revealed that VPA disrupts fatty acid beta-oxidation (beta-FAO) and leads to the accumulation of serum long-chain acylcarnitines (LCACs). Additionally, the study found that fenofibrate (Feno) can improve beta-FAO and protect against VPA-induced hepatotoxicity by activating PPAR alpha.