The Mechanism Of TFEB-Autophagy In The Treatment Of NAFLD With Fenofibrate

Objective:Fenofibrate is an agonist of peroxisome proliferation activated receptor alpha(PPARα).In recent years,it has been widely used in the treatment of hyperlipidemia and it has been well known.It has been confirmed that fenofibrate can alleviate lipid accumulation in non-alcoholic fatty liver disease(NAFLD).Autophagy for the treatment of liver diseases has always been a hot topic,but the specific mechanism is still unclear.This study aims to explore the beneficial effects for the treatment of NAFLD with fenofibrate and the possible mechanism of fenofibrate activating autophagy and alleviating lipid accumulation in NAFLD.Methods:We established the NAFLD mouse model through a high-fat diet(HFD).After the intervention of fenofibrate,liver tissue and serum were collected.Hepatic steatosis and lipid deposition were detected by HE staining and oil red O staining;TG concentration and insulin content in serum or liver were detected by ELISA;For further to study the mechanism of autophagy,detected the expression levels of p62,Atg7 and LC3-II by Western blotting that were autophagy-related proteins.And observed the ultrastructure of autophagy with transmission electron microscopy;Further detected the protein expression level of TFEB,the key transcription factor regulating autophagy,and assessed the mRNA levels of TFEB target genes by RT-PCR.Results:We found that while fenofibrate reduced lipid deposition,TG content and insulin resistance index in the liver of NAFLD mice,it also activated autophagy(autophagy related proteins LC3-II and Atg7 were increased while autophagy substrate protein p62 was decreased;The number of autophagic vesicles was increased),and promoted the TFEB protein levels in nuclear and the mRNA levels of its target genes(ctsb,atp6v0d1,hprt,mcolnl,ppp3ca).In NAFLD mice,after injection with adeno-associated virus expressing TFEB shRNA before fenofibrate treatment,the autophagy was inhibited,and lipid deposition,TG content and insulin resistance index were significantly increased;In contrast,after injection with adeno-associated virus overexpressing TFEB,the autophagy was activated,and lipid deposition,TG content and insulin resistance index were significantly reduced.Conclusion:These results suggest that fenofibrate activates autophagy through TFEB,and the reduction of lipid accumulation in the livers of NAFLD mice depends on TFEB and Atg7.This study provides a new evidence for the mechanism of treatment for NAFLD with fenofibrate.