The elucidation of the mechanisms whereby the liver maintains glucose homeostasis is crucial for the understanding of physiologic and pathologic 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 physiologic fasting and feeding.
There are no sequencing or structural data generated in this manuscript. All data generated and analyzed are included in the manuscript.
- Ji Miao
- Ji Miao
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animal experiments were performed with the approval of the Institutional Animal Care and Research Advisory Committee at Boston Children's Hospital (protocols 17-07-3413R and 20-07-4200R).
- David E James, The University of Sydney, Australia
- Received: April 1, 2020
- Accepted: August 13, 2021
- Accepted Manuscript published: October 8, 2021 (version 1)
© 2021, Xu et al.
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