Effects Of Pegylated Curcumin Derivative On Non-alcoholic Fatty Liver

ObjectivesCurcumin has the potential to cure dyslipdemia and nonalcoholic fatty liver disease(NAFLD),however,its therapeutic effects are curbed on account of poor bioavailability.Our previous study has shown that modification of curcumin with polyethylene glycol(PEG)improves blood concentration and tissue distribution.This study aimed to investigate the roles of a novel PEGylated curcumin derivative(Curc-mPEG454)in regulating lipid metabolism and hepatic steatosis,and to elucidate the underlying molecular mechanism in high fat diet(HFD)-fed C57BL/6J mice model.MethodsForty male 6-8 week old C57BL/6J mice were randomly into 4 groups: mice were fed with chow diet(D12450B)as control,HFD(D12492)as NAFLD model and mice fed a HFD with Curc-mPEG454 by intraperitoneal injection 50mg/kg or 100mg/kg for 16 weeks as treatment groups.At the end of the experiment,the body weight,liver weight and levels of serum ALT,AST,total cholesterol(TC),triglycerides(TG),low density lipoprotein cholesterol(LDL-C)and high density lipoprotein cholesterol(HDL-C)were measured.HE and Oil red O staining were used to evaluate the extent of hepatic steatosis.The m RNA expression of genes involved in hepatic lipogensis,FA uptake,FA oxidation,TG secretion,and bile acid synthesis were detected by real time PCR.The protein expression of CD36,PPARγ,CREB and P-CREB were detected by western blotting and immunohistochemical staining.Results1.The effect of Curc-mPEG454 on body weight and plasma TG level: After 16 weeks of experiment treatment,HFD induced significant elevation of final body weight,body weight gain,and liver weight compared with the chow diet group.Curc-mPEG454 treatment(50mg/kg and 100mg/kg)apparently lowered the final body weight and body weight gain compared to these in the HFD group,but there was no dose-dependent difference observed between these two groups.In addition,Curc-mPEG454 significantly lowered the plasma TG compared with the HFD group,but did not apparently affect plasma TC,HLD-C,LDL-C and FFA levels.These results illustrated that Curc-mPEG454 effectively lowered plasma TG and corrected for hypertriglyceridemia2.Curc-mPEG454 attenuates hepatic lipid accumulation: H&E and Oil red O showed that mice fed with the HFD developed severe macro-and microvescicular steatosis without apparent inflammatory cell infiltration and fibrosis,while Curc-mPEG454 treatment obviously attenuated the state of steatosis with a notable reduction in the number of vacuolar area.Also,the degree of steatosis in HFD group were mainly distributed in grade 3 and 4,while significantly attenuated to grade 1 and 2 by Curc-mPEG454 treatment according to Kirsch standard.Consistent with these results,the TG content in liver was significantly decreased after Curc-mPEG454 supplementation.These results indicated that Curc-mPEG454 may effectively protect against hepatic steatosis and TG accumulation induced by HFD.3.Effect of Curc-mPEG454 on attenuating lipid metabolism: Curc-mPEG454 suppressed the HFD-induced up-regulation expression of CD36 and hepatic peroxisome proliferator activated receptor γ(PPARγ),a positive regulator of CD36.Moreover,Curc-mPEG454 dramatically activated c AMP response element binding protein(CREB),which negatively control hepatic PPARγ expression.Curc-mPEG454 has no effects on the genes involved in hepatic lipogenesis,FA oxidation,TG secretion and bile acid synthesis.Conclusions1.Curc-mPEG454 can decrease the body weight and liver weight,reduce the serum and liver levels of TG,attenuates liver lipid accumulation.2.Curc-mPEG454 reverses HFD-induced hepatic steatosis by activat-ing the CREB/PPARγ/CD36 pathway,which may be an effective therapeutic for high fat diet-induced NAFLD.