Background and aims:Primary sclerosing cholangitis(PSC)is an autoimmune liver disease characterized by complex pathogenesis and limited available therapeutic options.The mechanisms underlying the development and progression of PSCs remain unclear.Liver X receptor beta(LXR-β)is recognized to modulate lipid metabolism and immune response,but its specific involvement in the PSC has not been elucidated.Here,we explored the role and mechanism of LXR-β in PSC induced by 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-collidine(DDC).Methods:CRISPR-Cas9 technology was applied to generate Abcb4(coding MDR2,next named as Mdr2),Nr1h2(coding LXR-β,next named as Lxrβ),and Rag2(coding RAG2)knockout mice.DDC was used to induce PSC.Hematoxylin and eosin and Sirius red staining were used to assess the extent of hepatic injury and fibrosis.Flow cytometry was used to observe immune cell subsets.Results:We observed a declining trend in hepatic Lxrβ in the PSC model.Unexpectedly,Lxrβ knockout failed to modulate DDC-induced PSC pathogenesis.Concomitantly,assessment of the influence of Rag2 deficiency on PSC progression revealed the absence of aggravated or alleviated hepatic injury or fibrosis in the Rag2-/-DDC mice.However,Lxrβ depletion intensified DDC-induced PSC in the Rag2-/-mice,with more abundant infiltrative inflammatory cells and more severe liver fibrosis.Compared with Rag2-/-DDC mice,Lxrβ-/-Rag2-/-DDC mice had higher serum ALT and AST levels and mRNA expression of proinflammatory and profibrotic genes.Flow cytometry showed that LXR-β deficiency resulted in a diminished population of hepatic innate immune cells.Conclusion:This study indicated innate immune cell LXR-β deficiency can exacerbate hepatic injury and fibrosis in murine models of PSC suggesting that LXR-β may regulate the function of innate immunity in the fibrotic advancement of PSC.

Objective:To study the relationship and the role of leptin in children with biliary atresia and hepatic fibrosis to provide a treatment basis for these patients.Methods:The clinical data of children with biliary atresia or congenital biliary dilatation (CBD) who underwent surgical treatment at the Department of General Surgery of Tianjin Children's Hospital from August 2019 to August 2021 were retrospectively analyzed. Of 31 children included in this study, there were 14 males and 17 females, with age of 60 (30, 63) d. Children with biliary atresia served as the study group ( n=26) and children with CBD served as the control group ( n=5). Leptin protein, α-smooth muscleactin (α-SMA) and phosphorylation of extracellular-regulated protein kinase 1/2 (p-ERK1/2) in liver tissues were detectd by immunohistochemistry (IHC). The expression level of leptin mRNA in liver tissues were detected by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Results:The average optical density values of leptin protein, α-SMA protein and p-ERK1/2 protein in the liver tissues of children in the study group were significantly higher than the control group ( P<0.05). The expression levels of leptin, α-SMA and p-ERK1/2 in liver tissues of children with biliary atresia significantly increased with increase in fibrosis degree ( P<0.05). The expression level of leptin in liver tissues of children with biliary atresia was positively correlated with the liver fibrosis grade ( rs=0.876), α-SMA ( r=0.723) and p-ERK1/2 ( r=0.725) ( P<0.01). The results of qRT-PCR showed that the content of leptin mRNA in liver tissues of children with biliary atresia was significantly higher than that of children with CBD ( P<0.05). Conclusion:Expressions of leptin increased with aggravation of degrees of hepatic fibrosis in biliary atresia. Leptin may be involved in activation of HSCs through the ERK1/2 signaling pathway in the process of hepatic fibrosis due to biliary atresia.