Study On The Effect And Mechanism Of Bavachinin On Non-Alcoholic Fatty Acid Disease

ObjectiveWith changes in lifestyle and dietary structure,the incidence of non-alcoholic fatty liver disease（NAFLD）has increased and become a global health problem.There is none drug has been approved by FDA for the treatment of NAFLD.Bavachinin（BVC）is a flavanone isolated from Psoralea corylifolia L,which has been reported that have inhibitory effects on neuroinflammation and asthma.We previously reported that BVC as a natural pan-PPAR agonist,exhibited beneficial effect on insulin resistance and lipid metabolism in both dietary（HFD）and genetic（db/db）obesity model.Insulin resistance（IR）and inflammation play a crucial role in the development and progression of NAFLD.BVC might have beneficial effects on NAFLD,because of the effects of BVC on anti-inflammation and glucose and lipid homeostasis.In our study,we evaluate the effect of BVC on the different stage of NAFLD in three murine models（HFD,MCD and CCl₄ model）.In addition,LPS-stimulated RAW264.7 cells were used to evaluate the anti-inflammation effect of BVC on macrophage.Methods1.HFD model was used to estimate the hepatoprotective activity of BVC hepatic steatosis.To explore the mechanism of BVC ameliorates hepatic steatosis,the expression levels of lipids metabolism-related genes in the liver,white adipose tissue and small intestine were measured by RT-PCR.2.MCD model was used to evaluate the efficacy of BVC on MCD induced liver steatosis,liver inflammation and early fibrosis were measured.RT-PCR was used to evaluate the effect of BVC on the expression of genes involved in hepatic lipid metabolism,proinflammation and pro-fibrogenesis in MCD induced mice.3.CCl₄induced murine experimental liver fibrosis model was used to evaluate the effect of BVC on established liver fibrosis.RT-PCR was used to evaluate the effect of BVC on the expression of proinflammation and pro-fibrogenesis genes.4.LPS-stimulated RAW264.7 cells were used to study the anti-inflammatory effect of BVC on macrophages.Western blot was used to explore the effect of BVC on MAPK or NF-κB signaling pathway.Dual luciferase reporter was used to evaluate the effect of BVC on the TNFα-induced NF-κB transcriptional activation.Results1.BVC reduced the elevated fasting blood glucose（FBG）and serum TG levels in HFD mice without affecting food intake and body weight.BVC reduced the liver weight,（liver weight/body weight）percentage,liver TG,TC content,and lipid droplet accumulation in the liver.BVC effectively improved liver steatosis by increasing the expression of liver fatty acid（FFA）oxidation genes,without affecting the de novo synthesis of lipids and liver TG secretion.BVC also increased the expression of PPARγtarget genes CD36 and ACOX1 in the WAT,and the expression of PPARαand ACOX1in the small intestine.BVC also decreased the expression of inflammatory genes and macrophage marker.2.BVC significantly improved the expression of liver inflammation and inflammatory genes,and had a certain protective effect on the formation of early liver fibrosis.BVC mildly improved liver MCD diet-induced liver steatosis and tended to reduce serum ALT levels.3.BVC reduced liver collagen deposition and liver hydroxyproline content,and inhibited the expression of fibrosis and inflammation-related genes.However,BVC did not reduce serum liver function related indexes in CCl₄mice.4.BVC reduced LPS-stimulated RAW264.7 cells expression and secretion of inflammatory factors.BVC reduced p38 and JNK phosphorylation,but did not affect ERK phosphorylation and IκBαdegradation.BVC did not decrease TNFαinduced NF-κB transcriptional activity.ConclusionBVC exhibited antisteatotic effect in HFD mice partly through activating hepatic PPARαand increasing FFA oxidation.BVC also reduced intestinal lipid absorption by activating PPARαin the small intestine.In addition,BVC inhibited lipolysis by activating PPARγin the white adipose tissues which contribute to decrease lipid accumulation in the liver.BVC significantly improved liver lobular inflammation and mildly improved liver steatosis in MCD model.BVC reversed the established liver fibrosis in CCl₄model.BVC had protective effect on the various stages of NAFLD progression,suggesting that BVC could be a potential candidate compound for the treatment of NAFLD.BVC inhibited the phosphorylation of p38 and JNK without affecting ERK phosphorylation.BVC had no effect on the degradation of IκBαand the transcriptional activity of NF-κB.BVC exhibited anti-inflammatory via modulating p38and JNK signaling pathways.