Short-term tamoxifen administration improves hepatic steatosis and glucose intolerance through JNK/MAPK in mice  

作　　者：Zhiqiang Fang Hao Xu Juanli Duan Bai Ruan Jingjing Liu Ping Song Jian Ding Chen Xu Zhiwen Li Kefeng Dou Lin Wang 

机构地区：[1]Department of Hepatobiliary Surgery,Xi-Jing Hospital,Fourth Military Medical University,Xi’an 710032,China [2]Center of Clinical Aerospace Medicine&Department of Aviation Medicine,Fourth Military Medical University,Xi’an 710032,China

出　　处：《Signal Transduction and Targeted Therapy》2023年第4期1842-1856,共15页信号转导与靶向治疗（英文）

基　　金：The National Key Research and Development Program of China(2016YFA0102100,2021YFA1100500);NSFC 81800533,81870430,81422009,81770560。

摘　　要：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.

关 键 词：TAMOXIFEN HEPATIC inflammation 

分 类 号：R575[医药卫生—消化系统]