Silybin alleviates hepatic lipid accumulation in methionine-choline deficient diet-induced nonalcoholic fatty liver disease in mice via peroxisome proliferator-activated receptorα  

作　　者：CUI Shuang PAN Xiao-Jie GE Chao-Liang GUO Yi-Tong ZHANG Peng-Fei YAN Ting-Ting ZHOU Ji-Yu HE Qing-Xian CHENG Long-Hao WANG Guang-Ji HAO Hai-Ping WANG Hong 

机构地区：[1]State Key Laboratory of Natural Medicines,Key Laboratory of Drug Metabolism&Pharmacokinetics,China Pharmaceutical University,Nanjing 210009,China [2]Department of Pharmacy,The First Affiliated Hospital of Anhui Medical University,Hefei 230022,China [3]Laboratory of Metabolism,Center for Cancer Research,National Cancer Institute,National Institutes of Health,Bethesda,MD 20892,USA

出　　处：《Chinese Journal of Natural Medicines》2021年第6期401-411,共11页中国天然药物（英文版）

基　　金：supported by the National Natural Science Foundation of China(Nos.81720108032,81930109,82073926,82073928);the Project for Major New Drug Innovation and Development(Nos.2018ZX09711001-002-003,2018ZX09711002-001-004);Overseas Expertise Introduction Project for Discipline Innovation(No.G20582017001).

摘　　要：Nonalcoholic fatty liver disease(NAFLD)is regarded as the most common liver disease with no approved therapeutic drug currently.Silymarin,an extract from the seeds of Silybum marianum,has been used for centuries for the treatment of various liver diseases.Although the hepatoprotective effect of silybin against NAFLD is widely accepted,the underlying mechanism and therapeutic target remain unclear.In this study,NAFLD mice caused by methionine-choline deficient(MCD)diet were orally administrated with silybin to explore the possible mechanism and target.To clarify the contribution of peroxisome proliferator-activated receptorα(PPARα),PPARαantagonist GW6471 was co-administrated with silybin to NAFLD mice.Since silybin was proven as a PPARαpartial agonist,the combined effect of silybin with PPARαagonist,fenofibrate,was then evaluated in NAFLD mice.Serum and liver samples were collected to analyze the pharmacological efficacy and expression of PPARαand its targets.As expected,silybin significantly protected mice from MCD-induced NAFLD.Furthermore,silybin reduced lipid accumulation via activating PPARα,inducing the expression of liver cytosolic fatty acid-binding protein,carnitine palmitoyltransferase(Cpt)-1a,Cpt-2,medium chain acyl-CoA dehydrogenase and stearoyl-CoA desaturase-1,and suppressing fatty acid synthase and acetyl-CoA carboxylaseα.GW6471 abolished the effect of silybin on PPARαsignal and hepatoprotective effect against NAFLD.Moreover,as a partial agonist for PPARα,silybin impaired the powerful lipid-lowering effect of fenofibrate when used together.Taken together,silybin protected mice against NAFLD via activating PPARαto diminish lipid accumulation and it is not suggested to simultaneously take silybin and classical PPARαagonists for NAFLD therapy.

关 键 词：SILYBIN NAFLD PPARa Lipid metabolism FENOFIBRATE 

分 类 号：R965[医药卫生—药理学]