Abstract
Valproic acid (VPA) is one of the most widely prescribed antiepileptic drugs, as VPA-induced hepatotoxicity is one of the most severe adverse reaction that can lead to death. The objective of this study was to gain an understanding of dysregulated lipid metabolism in mechanism of hepatotoxicity. Nontargeted lipidomics analysis with liquid chromatography–quadrupole-time-of-flight mass spectrometry (LC-Q-TOF/MS) was performed to explore differential lipids from the patient serum and L02 cells. Lipidomics data interpretation was augmented by gene expression analyses for the key enzymes in lipid metabolism pathways. From patient serum lipidomics, pronouncedly changed lipid species between abnormal liver function (ALF) patients and normal liver function (NLF) patients were identified. Among these lipid species, LPCs, Cers, and SMs were markedly reduced in the ALF group and showed negative relationships with liver injury severity [alanine aminotransferase (ALT) levels], while significantly increased triacylglycerols (TAG) with higher summed carbon numbers demonstrated a positive relationship with ALT levels. Regarding lipidomics in hepatic L02 cells, TAG was markedly elevated after VPA exposure, especially in TAGs with more than 53 summed carbons. Besides, gene expression analysis revealed dysregulated lipid metabolism in VPA-treated L02 cells. Peroxime proliferators-activated receptor (PPARγ) pathway played an important role in VPA-induced lipid disruption through inducing long-chain fatty acid uptake and TAG synthesis, which was also regulated by Akt pathway. Our findings present that VPA-induced lipid metabolism disruption might lead to lipotoxicity in the liver. This approach is expected to be applicable for other drug-induced toxicity assessments.
Highlights
Valproic acid (VPA) is an antiepileptic drug (AED) that is widely used in the treatment for epileptic children and is effective against many types of seizure disorders either alone or as a component of a multidrug regimen (Bűdi et al, 2015)
We found that the Akt–PPARγ pathway participated in VPA-induced lipid disruption, which acts as a critical pathway in the regulation of adipose differentiation, lipid storage, and genes involved in energy storage and utilization (Rogue et al, 2010)
All patients enrolled in the abnormal liver function (ALF) group were diagnosed with ALF according to ALT and AST levels (ALT > 2 × upper limit of normal (ULN) and/or AST > 2 × ULN), which are considered good indicators of liver cell damage; ALT is considered as more specific for liver injury than AST
Summary
Valproic acid (VPA) is an antiepileptic drug (AED) that is widely used in the treatment for epileptic children and is effective against many types of seizure disorders either alone or as a component of a multidrug regimen (Bűdi et al, 2015). Previous studies had revealed that the hepatotoxic metabolites of VPA played a critical role in its pathogenesis (Park et al, 2005; Walgren et al, 2005). It is critical to identify noninvasive biomarkers (indicators of adverse effects) for the early diagnosis of liver injury induced by VPA prior to the occurrence of irreversible damage. Huo et al (2014) indicated that VPA-induced hepatotoxicity disrupted glycolysis, lipid metabolism, and amino acid metabolism in humans through metabolomic approach. Several metabolomic studies found disrupted glycine in serum and hippuric acid in rat urine, which were considered as VPA-induced hepatotoxicity biomarkers (Lee et al, 2009; Sun et al, 2010; Zhang et al, 2014)
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