Syringin alleviates hepatic fibrosis by enhancing autophagic flux and attenuating ER stress-TRIB3/SMAD3 in diabetic mice
Tissue and Cell(2023)
Abstract
Type 2 diabetes mellitus (T2DM) is a key risk factor for the developing of metabolic liver injury and easily evolving to advanced fibrosis. Syringin (SYR), isolated from Acanthopanax senticosus, has anti-inflammatory, antioxidant, and anti-apoptotic properties. However, its hepatoprotective effects and mechanisms in T2DM-induced liver fibrosis remain unclear. Here, we investigated whether syringin (SYR) could serve as a therapeutic agent for liver fibrosis and its mechanism in high-fat diet (HFD)/streptozotocin (STZ)-induced type 2 diabetic mice. C57BL/6 mice were induced with T2DM via HFD and STZ injection and treated with different doses of SYR. Serum lipid parameters and liver function indicators were measured, and hepatic histology and fibrosis were examined. The mechanism of SYR was explored through molecular analyses Results demonstrated SYR improved oral glucose tolerance, decreased the levels of ALT, AST, and AKP, and reduced hepatic lipid deposition in diabetic mice. Moreover, SYR ameliorated epithelial-to-mesenchymal transition to reverse hepatic fibrosis via suppressing TRIB3-SMAD3 interaction to restrain nuclear localization of SMAD3. Strikingly, SYR reversed hyperglycemia-induced deficiency in autophagic flux by regulation of Raptor/mTORC1, triggering nuclear translocation of TFEB to improve autophagosome-lysosomal fusion. In brief, SYR potentially ameliorates hepatic injury and fibrosis by enhancing autophagic flux and inhibing TRIB3 activation in diabetic mice.
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Key words
AKP,ALT,AS,AST,ATF4,Atg7,BCA,BDL,BIP,CHOP,DAPI,DM,E-Ca,EMT,ER,ER stress,ERK1/2,GSP,H&E,HCC,HDL-C,HFD,HSCs,LAMP1,LC3,LDL-C,LPS/D-GalN,mTORC1,NAFLD,NASH,NF-κB,OA,OGTT,p-PERK,PSR,PVDF,qRT-PCR,PCR ROS,SDS-PAGE,SIRT1,SQSTM1,STZ,T2DM,TAA,TC,TFEB,EB TG,TGF-β,TLR4,α-SMA
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