Nonalcoholic fatty liver disease (NAFLD) which is a leading cause of chronic liver diseases lacks effective treatment. Tamoxifen hasbeen proven to be the first-line chemotherapy for several solid tumors in clinics, ho...Nonalcoholic fatty liver disease (NAFLD) which is a leading cause of chronic liver diseases lacks effective treatment. Tamoxifen hasbeen proven to be the first-line chemotherapy for several solid tumors in clinics, however, its therapeutic role in NAFLD has neverbeen elucidated before. In vitro experiments, tamoxifen protected hepatocytes against sodium palmitate-induced lipotoxicity. Inmale and female mice fed with normal diets, continuous tamoxifen administration inhibited lipid accumulation in liver, andimproved glucose and insulin intolerance. Short-term tamoxifen administration largely improved hepatic steatosis and insulinresistance, however, the phenotypes manifesting inflammation and fibrosis remained unchanged in abovementioned models. Inaddition, mRNA expressions of genes related to lipogenesis, inflammation, and fibrosis were downregulated by tamoxifentreatment. Moreover, the therapeutic effect of tamoxifen on NAFLD was not gender or ER dependent, as male and female mice withmetabolic disorders shared no difference in response to tamoxifen and ER antagonist (fulvestrant) did not abolish its therapeuticeffect as well. Mechanistically, RNA sequence of hepatocytes isolated from fatty liver revealed that JNK/MAPK signaling pathwaywas inactivated by tamoxifen. Pharmacological JNK activator (anisomycin) partially deprived the therapeutic role of tamoxifen intreating hepatic steatosis, proving tamoxifen improved NAFLD in a JNK/MAPK signaling-dependent manner.展开更多
Liver sinusoidal endothelial cells(LSECs)play a pivotal role in maintaining liver homeostasis and influencing the pathological processes of various liver diseases.However,neither LSEC-specific hallmark genes nor a LSE...Liver sinusoidal endothelial cells(LSECs)play a pivotal role in maintaining liver homeostasis and influencing the pathological processes of various liver diseases.However,neither LSEC-specific hallmark genes nor a LSEC promoter-driven Cre mouse line has been introduced before,which largely restricts the study of liver diseases with vascular disorders.展开更多
基金The National Key Research and Development Program of China(2016YFA0102100,2021YFA1100500)NSFC 81800533,81870430,81422009,81770560。
文摘Nonalcoholic fatty liver disease (NAFLD) which is a leading cause of chronic liver diseases lacks effective treatment. Tamoxifen hasbeen proven to be the first-line chemotherapy for several solid tumors in clinics, however, its therapeutic role in NAFLD has neverbeen elucidated before. In vitro experiments, tamoxifen protected hepatocytes against sodium palmitate-induced lipotoxicity. Inmale and female mice fed with normal diets, continuous tamoxifen administration inhibited lipid accumulation in liver, andimproved glucose and insulin intolerance. Short-term tamoxifen administration largely improved hepatic steatosis and insulinresistance, however, the phenotypes manifesting inflammation and fibrosis remained unchanged in abovementioned models. Inaddition, mRNA expressions of genes related to lipogenesis, inflammation, and fibrosis were downregulated by tamoxifentreatment. Moreover, the therapeutic effect of tamoxifen on NAFLD was not gender or ER dependent, as male and female mice withmetabolic disorders shared no difference in response to tamoxifen and ER antagonist (fulvestrant) did not abolish its therapeuticeffect as well. Mechanistically, RNA sequence of hepatocytes isolated from fatty liver revealed that JNK/MAPK signaling pathwaywas inactivated by tamoxifen. Pharmacological JNK activator (anisomycin) partially deprived the therapeutic role of tamoxifen intreating hepatic steatosis, proving tamoxifen improved NAFLD in a JNK/MAPK signaling-dependent manner.
文摘Liver sinusoidal endothelial cells(LSECs)play a pivotal role in maintaining liver homeostasis and influencing the pathological processes of various liver diseases.However,neither LSEC-specific hallmark genes nor a LSEC promoter-driven Cre mouse line has been introduced before,which largely restricts the study of liver diseases with vascular disorders.