The Underlying Mechanisms Of Schisantherin A Against High Fat Diet Induced Non-Alcoholic Fatty Liver Disease Through The Regulation Of FXR Pathway

The accumulation of ectopic triglycerides in the liver is termed non-alcoholic fatty liver disease(NAFLD),it is currently the most common liver disease in the world.The pathogenesis of NAFLD from the simple steatosis to non-alcoholic hepatitis(NASH),then,liver fibrosis,liver cirrhosis,and finally to hepatocellular carcinoma(HCC),it is a huge threat to health.Farnesoid X receptor plays an important role in bile acid metabolism,glucose metabolism and lipid metabolism.It is an important target for the screening of hypoglycemic and lipid-lowering drugs.Traditional Chinese medicine become more and more attentioned because of its therapy on metabolic diseases such as nonalcoholic fatty liver disease.Schisandra Chinensis Baill,the mature fruit of Schisandrae chinensis fructusas,is native to northern and northeastern China,known as "Northern Schisandra".Moreover,growing evidence suggests potential benefits from Schisandra Chinensis Baill in protecting liver and anti-diabetes,but the active components and underlying mechanisms of hypoglycemic and lipid-lowering effects are still unclear.In the present study,we identified that Schisantherin A(SchA),the major active component of Schisandra Chinensis Baill,significantly activated FXR signaling by screening a library of natural products.Thus,we evaluated the efficacy in vivo,and further studied the primary function mechanism of SchA,and the obtained results are as following:1.The efficacy evaluation of Schisantherin A on high fat diet-induced NAFLDWe studied the metabolic improvement effects ofSchA by using diet-induced NAFLD animal model.The administration was lasted for six weeks with the doses 40 mg/kg and 80 mg/kg,respectively.SchA could strikingly inhibit the lipid accumulation in the liver and adipose tissue,decrease the body weight,improve the glucose ressistance and insulin ressistance in diet-induced NAFLD mouse without the changes of food intake.In addition,Sch A increased energy expenditure.2.The underlying mechanism of Schisintherin A on high fat diet-induced NAFLD.To investigate the target organ of Schisintherin A,we analyzed the distribution of SchA in vivo,and the results showed that the component was mainly distributed in liver,intestine,suggesting that these tissues are the mainly functional target tissues of Sch A.Considering the important roles of FXR in regulating bile acid homeostasis,we analyzed the bile acid metabolic profile in liver and serum after Sch A treatment,and the results showed that CDCA was significantly increased in liver and serum,which is the strongest activator of FXR.Furthermore,we detected FXR and its target genes,as well as downstream signaling associated genes in the liver after Sch A.treatment,and found that small heterodimer partner gene(SHP),an identified target gene of FXR,was significantly up-regulated,whereas cholesterol 7α-The hydroxylase CYP7A1,cholesterol 12α-hydroxylase(CYP8B1),and cholesterol-27 hydroxylase(CYP271)were significantly down-regulated.At the same time,Sch A negativelymodulateSREBP and its target genes in order to inhibit the hepatic lipid synthesis and improve liver steatosis of NAFLD.The direct regulation of FXR activity at transcriptional level was further verified by mouse primary hepatocytes in vitro.Collectively,the results indicated that,SchA,a major active component of Schisandra Chinensis Baill,can activated bile acid nuclear receptor to change the composition of bile acids in liver and serum,decrease the secondary/primary bile acid ratio,and strikingly increase chenod-eoxycholic acid(CDCA)and taurine-bound goose deoxygenation(TCDCA)which can also regulated SREBP and its target genes,contributing to the improved HFD-induced NAFLD and insulin resistance.