Gadd45b is required in part for the anti-obesity effect of constitutive androstane receptor(CAR)

• 作者: Xinran Cai Ye Feng Meishu Xu Chaohui Yu Wen Xie
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（2）
• 所属期刊栏目: Original articles
• 页码范围: 434-441
• 页数: 8页
• 语种: 英文

摘要

Crosstalk between xenobiotic metabolism and energy metabolism in the liver has provided a potential opportunity to target xenobiotic receptors to treat metabolic diseases.Activation of constitutive an-drostane receptor(CAR),a xenobiotic-sensing nuclear receptor,has been shown to inhibit obesity,suppress hepatic gluconeogenesis,and ameliorate hyperglycemia in rodent models of obesity and type 2 diabetes.However,the underlying molecular mechanism remains to be defined.The growth arrest and DNA damage-inducible gene 45b(Gadd45b),a well-known anti-apoptotic factor,has been shown to be an induc-ible coactivator of CAR in promoting rapid liver growth.It is unknown whether the effect of CAR on energy metabolism depends on GADD45B.In the present study and by using a high fat diet(HFD)-induced obesity model,we show that reduced body weight gain and improved insulin sensitivity by the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene(TCPOBOP)were markedly blunted in Gadd45b knockout mice.Mechanistically,the TCPOBOP-responsive inhibition of hepatic lipogenesis,gluconeogenesis,and adipose inflammation observed in wild type mice were largely abolished in Gadd45b knockout mice.We conclude that Gadd45b is required in part for the metabolic benefits of CAR activation.