The Role Of Neutral Sphingomyelinase-2/ceramide Pathway In Alleviating Hepatic Fibrosis Caused By Common Bile Duct Obstruction

Background and aimsChronic liver disease is a major global public health problem.Regardless of the etiology,chronic liver disease is characterized by chronic destruction of liver parenchyma,persistent inflammation,and liver fibrosis,of which liver fibrosis is the key.Liver fibrosis is a fibrous scar formed by the accumulation of extracellular matrix proteins(mainly type I and III cross-linked collagen)that replace damaged normal tissue.Reduce hepatotoxicity or cholestatic liver injury;To change the regulatory mechanism of resident hepatic macrophages kupfer cells and bone marrow recruited macrophages;Inducing apoptosis of hepatic astrocytes and inactivating activated hepatic astrocytes or fibroblasts can reduce hepatic fibrosis.However,the treatment of liver fibrosis is not satisfactory,and the pathogenesis of liver fibrosis remains unclear and needs further study.With the development of metabolomics and lipidomics,lipid spectrometry technology can quantitatively describe lipids and their functions.The cell membrane is regarded as a "fluid Mosaic" in which homogeneous phospholipid bilayer is the main component.The plasma membrane is aheterogeneous,dynamic entity containing a variety of lipid domains,such as lipid microdomains and rafts,that can exhibit different functional states.Signal proteins have been shown to reside in the raft,be transferred to the raft or be transferred from the raft into the cell during signal transmission,so changes in the raft structure of the plasma membrane affect intracellular signaling pathways and alter cell functions.The sphingomyelin-cholesterol microdomain is the lipid matrix that forms the membrane raft.The metabolism of ceramide from sphinolipin alters the dynamics of these rafts and alters cell signal transduction,leading to changes in important cellular processes such as apoptosis,growth arrest,senescence,differentiation,mediated immune response,and cell cycle arrest.Sphingolipids and ceramides are significantly associated with the development of various diseases,but the role of liver fibrosis has not been reported.This topic will focus on the study of liver fibrosis caused by ligation of the common bile duct in mice,and understand the characteristics of lipid changes in mice with liver fibrosis through lipid spectrum analysis.To study the role and mechanism of dyssphingolipid metabolism in liver fibrosis induced by bile duct injury in ligation mice,and to provide a new idea for clinical prevention and treatment of liver fibrosis.Methods1.The mouse liver fibrosis model was established by ligation of the common bile duct.2.The correlation between liver fibrosis and sphingolipid metabolism in mice was studied at the metabolite level by lipidomics and lipid analysis.3.Real-time PCR was used to detect the expression level of sphingolipid metabolism enzyme R-DNA,and the correlation between liver fibrosis and sphingolipid metabolism in mice was studied at the level of metabolic enzyme,and the sphingolipid metabolism enzyme with significant difference was screened out.4.Exogenous injection of drugs that interfere with the different sphingolipid metabolism enzymes to study the effects of the drugs on liver fibrosis.Results1.Mouse liver fibrosis model was successfully established by ligation of common bile duct:2.The changes of lipid metabolism in the liver of mouse hepatic fibrosis model were revealed,and the changes of sphingolipid metabolism pathway of ceramide production were found;3.In the study of metabolic enzyme level of sphingolipid metabolism changes,it was found that the expression level of neutral sphingolipinase-2 was significantly different in liver tissue;4.Exogenous injection of neutral sphingomyelinase-2 inhibitors can reduce liver fibrosis by inhibiting oxidative stress of liver cells.ConclusionsIn this study,we found that activation of lipid metabolism by hepatic fibrosis in mice increased ceramide production.Neutral sphingomyelinase-2 was the most significant enzyme in the synthesis of ceramide metabolic enzymes,and inhibition of neutral sphingomyelinase-2 reduced ceramide production and played a protective role in liver.This study may be a clinical therapeutic target for liver fibrosis and contribute to the development of new drug therapy.