TAZ inhibits glucocorticoid receptor and coordinates hepatic glucose homeostasis in normal physiological states

eLife

Cunchuan Wang¹  Hong Kang²  Yibo Xiong³  Oliver Stöhr³  Kyle D Copps³  Morris F White³  Li He³  Lingyun Zheng³  Yangyang Liu⁴  Liang Chen⁵  Min Wang⁶  Ruixiang Hu⁷  Ji Miao⁸  Songjie Cai⁹  Simiao Xu^1,10 

[1] Department of Gastrointestinal Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China;Department of Systemic Biology, Harvard Medical School, Boston, United States;Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, United States;Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, United States;Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, United States;College of Science, Northeastern University, Boston, United States;Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, United States;Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;Department of Pathology, Beth Israel Deaconess Medical Center, Boston, United States;Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, United States;Department of Gastrointestinal Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China;Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, United States;Department of Pediatrics, Harvard Medical School, Boston, United States;Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, United States;Transplantation Research Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States;Division of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Branch of the National Clinical Research Center for Metabolic Disease, Wuhan, China;Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, United States;

关键词: hippo pathway effector;    transcriptional co-activator with PDZ-binding motif;    hepatic gluconeogenesis;    glucocorticoid receptor;    fasting and feeding;    Mouse;   

DOI  :  10.7554/eLife.57462

来源: eLife Sciences Publications, Ltd

【 摘 要 】

The elucidation of the mechanisms whereby the liver maintains glucose homeostasis is crucial for the understanding of physiological and pathological states. Here, we show a novel role of hepatic transcriptional co-activator with PDZ-binding motif (TAZ) in the inhibition of glucocorticoid receptor (GR). TAZ is abundantly expressed in pericentral hepatocytes and its expression is markedly reduced by fasting. TAZ interacts via its WW domain with the ligand-binding domain of GR to limit the binding of GR to the GR response element in gluconeogenic gene promoters. Therefore, liver-specific TAZ knockout mice show increases in glucose production and blood glucose concentration. Conversely, the overexpression of TAZ in mouse liver reduces the binding of GR to gluconeogenic gene promoters and glucose production. Thus, our findings demonstrate that hepatic TAZ inhibits GR transactivation of gluconeogenic genes and coordinates gluconeogenesis in response to physiological fasting and feeding.

【 授权许可】

CC BY