Xu Shansen, Chen Yanan, Ma Yiyi, Liu Ting, Zhao Mingming, Wang Zhanyou, Zhao Limei
Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, China.
Shanghai AB Sciex Analytical Instrument Trading Co. Ltd., Shanghai, China.
Front Pharmacol. 2019 Jul 19;10:819. doi: 10.3389/fphar.2019.00819. eCollection 2019.
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.
丙戊酸（VPA）是处方最广泛的抗癫痫药物之一，因为VPA诱导的肝毒性是最严重的不良反应之一，可导致死亡。本研究的目的是了解肝毒性机制中脂质代谢失调的情况。采用液相色谱 - 四极杆 - 飞行时间质谱（LC-Q-TOF/MS）进行非靶向脂质组学分析，以探索患者血清和L02细胞中的差异脂质。通过对脂质代谢途径中关键酶的基因表达分析来增强脂质组学数据的解读。从患者血清脂质组学中，鉴定出肝功能异常（ALF）患者和肝功能正常（NLF）患者之间明显变化的脂质种类。在这些脂质种类中，溶血磷脂酰胆碱（LPCs）、神经酰胺（Cers）和鞘磷脂（SMs）在ALF组中显著降低，并与肝损伤严重程度[丙氨酸氨基转移酶（ALT）水平]呈负相关，而总碳原子数较高的三酰甘油（TAG）显著增加，与ALT水平呈正相关。关于肝L02细胞的脂质组学，VPA暴露后TAG显著升高，尤其是总碳原子数超过53的TAG。此外，基因表达分析显示VPA处理的L02细胞中脂质代谢失调。过氧化物酶体增殖物激活受体（PPARγ）途径通过诱导长链脂肪酸摄取和TAG合成在VPA诱导的脂质紊乱中起重要作用，这也受Akt途径调节。我们的研究结果表明，VPA诱导的脂质代谢紊乱可能导致肝脏中的脂毒性。这种方法有望适用于其他药物诱导的毒性评估。
