Study On The Effects Of Fbxw5 On Nonalcoholic Steatohepatitis

Non-alcoholic steatohepatitis(NASH),which is a chronic liver injury or inflammation caused by the accumulation of excessive lipids in the liver,has become a major cause of chronic liver disease in adults.The main features of NASH are steatosis,lobular inflammation and hepatocyte ballooning with or without liver fibrosis,which is likely to develop into cirrhosis and liver cancer.NASH is associated with obesity,dyslipidemia and type 2 diabetes.Currently,there are no effective therapeutic drugs approved by Food and Drug Administration(FDA)for NASH.Therefore,a large amount of research is still needed to find effective therapeutic targets and therapeutic drugs.It has been reported that E3 ubiquitin ligase and deubiquitinating enzyme have a positive regulatory effect on NASH.Fbxw is the central component of the SCF E3 ligase complex.Our earlier experimental results suggest that SCF-Fbxw5 is likely to regulate NASH,so we explored the effects of Fbxw5 on NASH from animal and cellular levels.Research indicates that the hepatocyte-specific overexpression of Fbxw5 exacerbates the dietation-induced systemic and hepatic metabolic disorders,whereas the hepatocyte-specific inactivation of Fbxw5 significantly impedes the progression of these abnormalities.In summary,we found that Fbxw5 is a key promoter of NASH disease progression.Methods: Constructed specific Fbxw5 gene knockout and transgenic mice;Established the in vitro and in vivo NASH model: high-fat and high-cholesterol diet-fed mice,palmitate-cultured mouse primary hepatocytes cell lines;Metabolic index assessment and serological testing in mouses: body weight,liver weight,blood glucose,serum insulin content,serum lipid content,serum inflammatory factor levels,serum liver enzyme test,glucose tolerance,insulin tolerance test;Pathology and immunohistochemistry in mouses;Results: Primary hepatocytes were isolated from 6-8-weekold male mice successfully and treated with palmitic acid(0.4 m M)in combination with oleic acid(0.8 m M)(PO)to mimic the in vivo hepatic steatosis model.The results showed that Fbxw5 deletion attenuated PO-induced lipid accumulation and inhibited the expression of pro-inflammatory factors.Hepatocyte-specific Fbxw5-knockout mice and Hepatocyte-specific Fbxw5-transgenic mice were successfully constructed.And the NASH model was established by feeding the mice a high-fat/high-cholesterol(HFHC)diet.The results showed that the overexpression of Fbxw5 exacerbated HFHC-induced hepatic steatosis,fibrosis and inflammation while Fbxw5 deficiency attenuated HFHC-induced hepatic steatosis,fibrosis and inflammation.Conclusions: Our study provides both in vitro and in vivo evidences that overexpression of hepatocyte-specific Fbxw5 aggravates NASH progression by exacerbating hepatic steatosis,inflammation,and fibrosis.