ABSTRACT
Studies have shown that there are differences between the sexes regarding to the occurrence and development of liver diseases, which may be associated with sex hormones. However, the mechanisms behind it are largely unknown. In this study, we first investigated the differences of liver injury between male and female mice, using the CCl4-induced liver injury mouse model. It showed that the liver damage of male mice was much more severe than that of female mice. Both the acute injury and fibrosis of the liver were reduced when androgens were depleted by castration of male mice. The vulnerability of male liver was associated with testis endocrine and excessive activation of inflammatory response in the liver. Castrated male mice with testosterone supplementation showed aggravated liver inflammatory response and fibrosis. The activity of NOD-like receptor protein 3 (NLRP3) inflammasome was increased when testosterone supplementation was provided. However, the enhanced inflammatory response and fibrosis due to testosterone supplementation were negated by inhibiting the activation of NLRP3 using the specific small molecule inhibitor MCC950. It suggests that testosterone is a key factor that influences liver injury by regulating the NLRP3 inflammasome activation-mediated inflammatory response.
Subject(s)
Chemical and Drug Induced Liver Injury/metabolism , Chemokine CCL4/pharmacology , Inflammasomes/drug effects , Liver Cirrhosis/metabolism , Liver/drug effects , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Testosterone/pharmacology , Animals , Chemical and Drug Induced Liver Injury/pathology , Disease Models, Animal , Inflammasomes/metabolism , Liver/metabolism , Liver/pathology , Liver Cirrhosis/pathology , Male , Mice , OrchiectomyABSTRACT
Epithelial morphogenesis is a common feature in various organs and contributes to functional formation. However, the molecular mechanisms behind epithelial morphogenesis remain largely unknown. Mammary gland is an excellent model system to investigate the molecular mechanisms of epithelial morphogenesis. In this study, we found that cysteine dioxygenase (CDO), a key enzyme in cysteine oxidative metabolism, was involved in mammary epithelial morphogenesis. CDO knockout (KO) females exhibited severe defects in mammary branching morphogenesis and ductal elongation, resulting in poor lactation. CDO contributes to the luminal epithelial cell differentiation, proliferation, and apoptosis mainly through its downstream product cysteine sulfinic acid (CSA). Exogenous supplementation of CSA not only rescued the defects in CDO KO mouse but also enhanced ductal growth in wild-type mouse. It suggests that CDO regulates luminal epithelial differentiation and regeneration via CSA and consequently contributes to mammary development, which raises important implications for epithelial morphogenesis and pathogenesis of breast cancer.
