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

Yangyang Liu,Ruixiang Hu,Simiao Xu,Li He,Songjie Cai,Morris F White,Yibo Xiong,Hong Kang,Lingyun Zheng,Min Wang,Oliver Stöhr,Ji Miao,Liang Chen,Cunchuan Wang,Kyle D Copps

doi:10.7554/elife.57462

Abstract

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.

Highlights

The liver plays a critical role in organismal energy homeostasis by regulating diverse biologic processes in response to nutrient availability[1]
Pck[1] and G6pc, but it inconsistently affected the expression of canonical transcriptional co30 activator with PDZ-binding motif (TAZ) and Yes-associated protein 1 (YAP) target genes involved 91 in cell proliferation[16], including connective tissue growth factor (Ctgf) and cysteine-rich angiogenic inducer 61 (Cyr61) (Figure 1–Figure supplement 1A–B)
YAP is expressed at low levels in normal hepatocytes, which is crucial to the maintenance of their 331 differentiated state[24]

Summary

Introduction

The liver plays a critical role in organismal energy homeostasis by regulating diverse biologic processes in response to nutrient availability[1]. The activation of hepatic gluconeogenesis is required for the supply of glucose to tissues with a high glucose demand, such as the brain, and for the maintenance of glucose homeostasis, whereas in the fed state gluconeogenesis is suppressed[2, 3]. Glucagon and glucocorticoids (GCs; in humans, cortisol; in mice, corticosterone; synthesized in the adrenal cortex) are hormones that are secreted during fasting and promote hepatic gluconeogenesis at multiple levels, including via gene transcription. Glucocorticoid receptor (GR, encoded by the NR3C1 gene) is a member of the nuclear receptor super-family[5] that is a key transcriptional regulator of gluconeogenic gene expression in the fasting state[6]. GR directly responds to increases in GC concentration by activating gluconeogenic gene transcription, and plays a permissive role in the glucagon-mediated transcriptional control of these genes. A single dose of a GR antagonist is sufficient to reduce hepatic glucose output in healthy humans[10]

Methods

Results

Conclusion