Liver Med23 ablation improves glucose and lipid metabolism through modulating FOX01 activity  

作　　者：Yajing Chu Leonardo Gomez Rosso Ping Huang Zhichao Wang Yichi Xu Xiao Yao Menghan Bao Jun Yan Haiyun Song Gang Wang 

机构地区：[1]State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China [2]Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China [3]CAS-MPG Partner Institute for Computational Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China

出　　处：《Cell Research》2014年第10期1250-1265,共16页细胞研究（英文版）

基　　金：We thank Drs Dang-Sheng Li, Yi Liu, Gen-Sheng Feng, and Arnie Berk for critical reading of the manuscript, Drs Li-Jian Hui, Bao-Liang Song, Yong Liu, Yi-Guo Wang, and Zhong-Zhou Yang for discussions, Jing-Wen Yin for knockout design, MARC of Nanjing University for help with generating the Med23flax mice, Xing Fu for technical help and analysis with RNA-Seq. This study was supported in part by grants from the Chinese Academy of Sciences （XDA01010401）, the Ministry of Science and Technology of China （2009CB941100 and 2011CB510104）, and the National Natural Science Foundation of China （81030047 to G W, and 31322039 to H S）.

摘　　要：Mediator complex is a molecular hub integrating signaling, transcription factors, and RNA polymerase II （RNAPII） machinery. Mediator MED23 is involved in adipogenesis and smooth muscle cell differentiation, suggesting its role in energy homeostasis. Here, through the generation and analysis of a liver-specific Med23-knockout mouse, we found that liver Med23 deletion improved glucose and lipid metabolism, as well as insulin responsiveness, and prevented diet-induced obesity. Remarkably, acute hepatic Med23 knockdown in db/db mice significantly improved the lipid profile and glucose tolerance. Mechanistically, MED23 participates in gluconeogenesis and cholesterol synthesis through modulating the transcriptional activity of FOXO1, a key metabolic transcription factor. Indeed, hepatic Med23 deletion impaired the Mediator and RNAPII recruitment and attenuated the expression of FOXO1 target genes. Moreover, this functional interaction between FOXO1 and MED23 is evolutionarily conserved, as the in vivo activities of dFOXO in larval fat body and in adult wing can be partially blocked by Med23 knockdown in Drosophila. Collectively, our data revealed Mediator MED23 as a novel regulator for energy homeostasis, suggesting potential therapeutic strategies against metabolic diseases.

关 键 词：FOXO1 liver Med23-knockout mice GLUCONEOGENESIS insulin resistance OBESITY diabetes 

分 类 号：Q581[生物学—生物化学] TS245.4[轻工技术与工程—制糖工程]