Therapeutidcal Effects Of Total Flavonoids Of Litsea Coreana Level On Nonalcoholic Steatohepatitis And Its Partly Mechanisms Of Action

Nonalcoholic fatty liver disease(NAFLD) is an emerging worldwide common problem that is frequently associated with obesity,hyperlipidemia and type 2 diabetes mellitus.This disease,with an unclear natural history,can be severe and is characterized by a wide spectrum of pathological lesions.It encompasses a spectrum of histopathology,ranging from steatosis to cirrhosis.Steatosis alone does not appear to be progressive,while nonalcoholic steatohepatitis(NASH) does,since the latter often progresses to more severe stages of liver injury such as fibrosis,cirrhosis and even hepatocellular carcinoma.Though NASH may proceed into end-stage liver disease,the optimal treatment has not been established.Therapeutical of hepatic steatosis may protect a large number of individuals at risk of advanced liver disease.Litsea coreana levevar(also called Hawk Tea),which is distributed in the southern part of China,has been widely used as a health promoting tea for several centuries. Previous study has showed that Hawk Tea has hypolipidemic effect in rats fed with high fat diet.It has been identified that flavonoids are the main chemical components of this plant,which possess antioxidant property.So the use of flavonoids in pharmaceutical preparation seems very attractive.The aim of the present study is to evaluate the therapeutical effects of TFLC on NASH and to analyze possible mechanisms of TFLC effects in rats fed with high fat diet.The main contents are divided into some sections as follows. 1.Therapeutical Effects of TFLC on Nonalcoholic Steatohepatitis The therapeutical effects of TFLC were evaluated in high fat emulsion induced NASH model in rat for 8 weeks.TFLC(100,200,400 mg/kg) was administrated via gavage daily after fed with high fat emulsion for 3 weeks.TFLC effectively reduced the high fat emulsion induced elevated liver index,serum ALT,AST,TC,TG LDL-C and FFA levels,hepatic TC,TG,and FFA content,and increased serum HDL-C level.TFLC was also found effectively increased the serum content of Leptin and insulin.Western blot analysis showed after TFLC treated for 8 weeks,the elevation of serum TNF-αwas significantly reduced.The histopathological analysis suggested that TFLC reduced the degree of hepatic steatosis,liver inflammation and necrosis in rats.TFLC was shown to downregulate the expression of collagenous fibers.RT-PCR analysis showed the increased expression ofα-SMA mRNA was reduced.These results suggest that TFLC has positively therapeutical effects on high fat emulsion induced rat NASH.2.The effects of TFLC on oxidization of high fat induced nonalcoholic steatohepatitis in ratsThe elevation of hepatic MDA and serum NO were significantly reduced and the reduction of liver SOD content was increased after TFLC treatment.Western blot analysis showed after TFLC treated for 8 weeks,the elevated expression of CYP2E1 was reduced.Electronic microscope examination suggested mitochondria in the rats fed the high-fat emulsion diet showed degenerative changes with rarefied matrix and loss of cristae.These changes were prominent in most of the mitochondria in the rats fed the high-fat emulsion diet,while the ultrastructural mitochondrial lesions were significantly lightened in the rats treated with TFLC.These results suggested the therapeutical effects of TFLC on nonalcoholic steatohepatitis might be associated with its antioxidant effects, suppress the elevated expression of CYP2E1 as well as protect ultrastructural mitochondrial lesions.3.The effects of TFLC on Kupffer cell functionsIn vitro,TFLC effectively repressed abnormally high level of TLR4 mRNA from Kupffer cell stimulated by LPS.Western blot analysis showed after TFLC treated for 8 weeks,the increased expression of Kupffer cell TLR4 and NF-κB were depressed. To sum up,TFLC has the therapeutical effects on experimental nonalcoholic steatohepatitis model.The results in vivo and in vitro suggested that its mechanism of action might be associated with its anti-oxidative activity,ability to regulate liquid metabolism,reduce NO and TNF-αproduction,down-regulate CYP2EI,TLR4,NF-κB andα-SMA expression.