内质网应激负调控因子SEL1L通过抑制PERK通路减轻小鼠肝纤维化OA

AIM:This study investigates the role of suppressor/enhancer of Lin-12-like(SEL1L),a negative regulatory factor of endoplasmic reticulum stress(ERS),in liver fibrosis using a mouse model induced by sodium arsenite(NaAsO2)and carbon tetrachloride(CCl4).Furthermore,we explored the regulatory mechanism of SEL1L on the protein kinase R-like endoplasmic reticulum kinase(PERK)signaling pathway in the context of hepatic fibrosis.METHODS:Liver fibrosis was induced in C57BL/6J mice via intraperitoneal injection of NaAsO2 or CCl4.The mice were randomly as-signed to the NaAsO2 model and phosphate-buffered saline(PBS)control groups or CCl4 model and olive oil control groups(n=15 per group).Pathological changes were evaluated using hematoxylin-eosin(HE)and Sirius red staining.The SEL1L,PERK and α-smooth muscle actin(α-SMA)expression was examined by laser confocal microscopy.In vitro,he-patic stellate cells(HSCs)were categorized into multiple treatment groups:normal,NaAsO2,transforming growth factor-β(TGF-β),NaAsO2+SEL1L overexpression control,NaAsO2+SEL1L overexpression,TGF-β+SEL1L overexpression con-trol,and TGF-β+SEL1L overexpression.Overexpression of SEL1L was achieved by lentiviral transfection.The expression of ERS-related proteins,including glucose-regulated protein 78(GRP78),PERK,phosphorylated PERK(p-PERK),ac-tivating transcription factor 4(ATF4),and glutamine-rich protein 1(QRICH1),was analyzed using Western blot.Mor-phological changes were observed using optical microscopy,and PERK expression was assessed by immunofluorescence microscopy.Protein docking analysis,co-immunoprecipitation,and ubiquitination assays were performed to evaluate the SEL1L-PERK interaction.RESULTS:In NaAsO2 and CCl4-induced liver fibrosis,the PERK pathway was activated,ac-companied by significant down-regulation of SEL1L expression(P<0.01).In vitro,NaAsO2 and TGF-β promoted ERS in HSCs,enhancing their activation and proliferation(P<0.01).Inhibition of ERS suppressed HSC activation(P<0.01).The SEL1L directly bound to PERK and facilitated its ubiquitin-mediated degradation.CONCLUSION:In liver fibrosis mouse models,SEL1L expression is down-regulated.The SEL1L alleviates fibrosis by inhibiting excessive activation of the PERK signaling pathway and suppressing HSC activation through direct binding to PERK and promoting its ubiquitina-tion and degradation.