OBJECTIVE To investigate the mechanism underlying valproate(VPA)-induced hepatic hepatotoxicity.METHODS C57B/6J mice were given VPA at500 mg·kg-1·d-1by intragastric administration for 14 consecutive days,while the control group received the same volume of physiologic saline by intragastric administration for same days.Mice were sacrificed 24 h after the last administration.Blood samples were collected for plasma biochemical assays.Liver was fixed in 10%neutral buffered formalin for histopathological analysis,and RNA extraction.mR NA for selected genes expression encoding proteins key to fatty acid synthesis,triglyceride synthesis,fatty acid oxidation,phosphatidylcholine synthesis,and lipid uptake were measured using quantitative real-time PCR.RESULTS We found that VPA treatment induced hepatic injury in mice as evidenced by increased ALP,ATP,ASP,GGT,and LDH.Histopathological analysis of the liver in mice treated with VPA showed increased microvesicular steatosis in cytoplasm.More importantly,VPA treatment increased the m RNA expressions of sterol regulatory element binding protein(SREBP)-1c,peroxisome proliferator-activated receptor(PPAR)γ,diacylgycerol acyltransferase(DGAT)2,and cluster of differentiation(CD)36,while the mR NA levels of stearoyl-Co A desaturase(SCD)1,DGAT1,liver X receptorsα(LXRα),carnitine palmitoyltransferase(CPT)1,malonyl coenzyme A decarboxylase(MCD),uncoupling protein(UCP)2,phosphatidylethanolamine N-methyltransferase(PEMT),and pregnenolone X receptor(PXR)displayed significant decrease.CONCLUSION Our data showed that VPA induced disruption of hepatic lipid homeostasis,which could be helpful for a better under-standing of the mechanism underlying VPA-induced hepatotoxicity and for a better use of VPA.
BAI Xu-pengHONG Wei-pengYU Wei-bangHUANG MinJIN Jing
