Regulatory Effects Of CDO And CSAD Genes On Mice Liver Tissue Regeneration

Tissue regeneration is closely related to organ development,damage repair,aging,tumorigenesis and organ degenerative diseases.The liver is one of the organs with the strongest regenerative capacity in animals and a good model for studying tissue regeneration and repair of organ damage.Cysteine dioxygenase（CDO）and cysteine sulfinate decarboxylase（CSAD）are the key enzymes for cysteine oxidative metabolism and taurine（TAU）synthesis and are highly expressed in the liver;cysteine sulfinate（CSA）and TAU are the main catalytic reaction products of CDO and CSAD,respectively,and CSA can be used as the substrate of the reaction catalyzed by CSAD.This study used CCl₄liver injury model,partial hepatectomy mouse model,CDO knockout（CDO KO）mouse,CSAD knockout（CSAD KO）mouse model combined with CSA and TAU compensation test to explore CDO and CSAD on mouse liver Regulation and mechanism of tissue regeneration.The main research results obtained are as follows:Effects of CDO and CSAD on liver development:This study first compared the liver tissue morphology of normal CDO KO,CSAD KO and wild-type（WT）mice.The results showed that the liver morphology and fibrosis of the three genotypes were not significantly different.This indicates that the absence of CDO and CSAD has no effect on liver development.The effects of CDO and CSAD on the repair of CCl4 liver injury:Using the model of liver injury induced by CCl4,it was found that the acute liver injury and liver tissue fibrosis in CDO KO mice were more severe than those in WT mice（P<0.01）,while CSAD KO The liver tissue damage was significantly weaker than that of WT mice（P<0.01）;and CDO KO mice liver parenchymal cell proliferation activity was significantly lower than that of WT and CSAD KO mice（P<0.01）.It shows that CDO knockout affects liver injury repair function,while CSAD KO promotes liver injury repair.The effects of CDO and CSAD on liver regeneration:To analyze the effects of CDO and CSAD on liver tissue regeneration,this study analyzed the differences in liver tissue regeneration between WT,CDO KO and CSAD KO mice using a liver 2/3resection-regeneration model.After partial hepatectomy（PH）,CDO KO mice died within 48 hours after surgery（n=15）,while the survival rates of CSAD KO and WT mice were higher（CSAD:36/45,WT:37/48）,It shows that CDO has a certain effect on liver tissue regeneration and liver function maintenance.The liver index of CSAD KO mice during partial hepatectomy/regeneration is similar to that of WT mice,and liver tissue regeneration can be completed within 1 week.The results of hepatocyte proliferation analysis showed that WT mice reached the peak of hepatocyte proliferation at 36 hours after surgery and were significantly higher than those of CDO KO and CSAD KO mice（P<0.05）.At 48 hours after surgery,hepatocytes of CSAD KO mice reached the peak.Analysis of the m RNA expression of liver regeneration-related genes in PH 24h mice revealed that the deletion of CDO and CSAD genes both resulted in significant down-regulation of TNFα,TGFβ1,HGF,IGF-1,and EGF（P<0.05）.The results showed that CDO and CSAD play an important role in regulating liver regeneration.The lack of CDO leads to a decrease in the survival rate of mice after liver resection.The absence of CSAD delays the liver regeneration process,but it can still complete liver regeneration.The effect of CSA and TAU on the repair of liver injury in CDO KO mice:According to the biochemical reaction catalyzed by CDO and CSAD and the previous research results of the research group,CDO knockout results in the lack of CSA and TAU in the body,while CSAD knockout results in the lack of TAU and CSA accumulation.To further analyze whether CDO and CSAD regulate liver injury repair and regeneration through their upstream and downstream molecules of the catalytic reaction,CDO KO mice were compensated for CSA and TAU based on the CCl4-induced liver injury model,respectively.The results showed that CSA can significantly attenuate acute liver injury and liver tissue fibrosis（P<0.01）and significantly promote hepatocyte proliferation（P<0.01）;TAU can promote hepatocyte proliferation and attenuate acute liver injury,but it is significantly lower than CSA.This indicates that CDO and CSAD may regulate liver injury repair and regeneration through CSA and TAU.In summary,this study used the CCl4-induced liver injury model and the liver2/3 resection-regeneration model to find that both CDO and CSAD are involved in regulating liver tissue injury repair and regeneration;the catalytic products of CDO and CSAD are both involved in regulation Liver injury repair and regeneration,and CSA has a more important role.This study provides a new theory for the intracellular cysteine oxidative metabolism pathway to repair and regenerate liver injury,and provides potential value for the treatment of liver diseases.