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 t...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.展开更多
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).
文摘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.
