Toxicol Appl Pharmacol. 2017 Jun 1;324:12-25. doi: 10.1016/j.taap.2017.03.022. Epub 2017 Mar 31.

Valproate induced hepatic steatosis by enhanced fatty acid uptake and triglyceride synthesis.

Bai X1, Hong W1, Cai P1, Chen Y1, Xu C1, Cao D2, Yu W1, Zhao Z2, Huang M1, Jin J3.

Author information

1School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.2School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, China.3School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China. Electronic address: jinjing@mail.sysu.edu.cn.

Abstract

Steatosis is the characteristic type of VPA-induced hepatotoxicity and may result in life-threatening hepatic lesion. Approximately 61% of patients treated with VPA have been diagnosed with hepatic steatosis through ultrasound examination. However, the mechanisms underlying VPA-induced intracellular fat accumulation are not yet fully understood. Here we demonstrated the involvement of fatty acid uptake and lipogenesis in VPA-induced hepatic steatosis in vitro and in vivo by using quantitative real-time PCR (qRT-PCR) analysis, western blotting analysis, fatty acid uptake assays, Nile Red staining assays, and Oil Red O staining assays. Specifically, we found that the expression of cluster of differentiation 36 (CD36), an important fatty acid transport, and diacylglycerol acyltransferase 2 (DGAT2) were significantly up-regulated in HepG2 cells and livers of C57B/6J mice after treatment with VPA. Furthermore, VPA treatment remarkably enhanced the efficiency of fatty acid uptake mediated by CD36, while this effect was abolished by the interference with CD36-specific siRNA. Also, VPA treatment significantly increased DGAT2 expression as a result of the inhibition of mitogen-activated protein kinase kinase (MEK) – extracellular regulated kinase (ERK) pathway; however, DGAT2 knockdown significantly alleviated VPA-induced intracellular lipid accumulation. Additionally, we also found that sterol regulatory element binding protein-1c (SREBP-1c)-mediated fatty acid synthesis may be not involved in VPA-induced hepatic steatosis. Overall, VPA-triggered over-regulation of CD36 and DGAT2 could be helpful for a better understanding of the mechanisms underlying VPA-induced hepatic steatosis and may offer novel therapeutic strategies to combat VPA-induced hepatotoxicity.

KEYWORDS:

CD36; DGAT2; Fatty acid; Hepatic steatosis; SREBP-1c; Valproate

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