TAZ inhibits glucocorticoid receptor and coordinates hepatic glucose homeostasis in normal physiological states
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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.
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###This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on May 7, 2020, follows.
Summary
In this study the authors have examined the role of TAZ in regulating hepatic gluconeogenesis. The authors show by genetically manipulating the hepatic levels of TAZ that TAZ acts as a repressor of gluconeogenic gene expression and in parallel this regulates hepatic glucose output either in response to a pyruvate tolerance test or to a bolus of glucagon. They go on to show that these effects are mediated via an interaction between the WW domain in TAZ and the glucocorticoid receptor that impairs the ability of the GR to bind to promoter regions. Intriguingly these effects were not observed with YAP another member of the Hippo pathway. These findings extend the expanding role of TAZ in hepatic metabolism. …
###This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on May 7, 2020, follows.
Summary
In this study the authors have examined the role of TAZ in regulating hepatic gluconeogenesis. The authors show by genetically manipulating the hepatic levels of TAZ that TAZ acts as a repressor of gluconeogenic gene expression and in parallel this regulates hepatic glucose output either in response to a pyruvate tolerance test or to a bolus of glucagon. They go on to show that these effects are mediated via an interaction between the WW domain in TAZ and the glucocorticoid receptor that impairs the ability of the GR to bind to promoter regions. Intriguingly these effects were not observed with YAP another member of the Hippo pathway. These findings extend the expanding role of TAZ in hepatic metabolism. This is an extremely thorough analysis of the role of TAZ in hepatic metabolism involving a series of in vivo and in vitro studies utilizing different approaches to perturb the expression of hepatic TAZ levels. Much of the biochemistry is convincing and the data are well presented. The referees were less enthusiastic about the physiological implications of the data.
Essential Revisions
The effects of TAZ overexpression were much more impressive than its under-expression when looking at PTT. In fact if it weren't for the almost non-existent error bars for each BG measurement on the PTT I would almost doubt there is much of a significant effect of TAZ KO. How do the authors explain this? Is this because the mice were so fasted that hepatic TAZ levels are already so low that further reduction in its expression has little effect? This raises the issue of how physiological the level of overexpression of TAZ was. In Figure 3, if I am to interpret this correctly, the level of TAZ in total liver was 3-fold higher in overexpressing mice than controls whereas in the pericentral regions it was expressed at comparable levels to endogenous. Does this mean that there is much TAZ expression in other parts of the liver where TAZ would normally not be found? This needs to be addressed in the manuscript.
It would be important to measure TAZ protein concentrations in liver of diabetic mouse models i.e hyperglycemic (genetic or nutritional models of diabetes and/or insulin resistance). Does TAZ affect the binding of GR to gluconeogenic gene promoters under hyperglycemic/diabetic conditions?
Would the overexpression of TAZ prevent the hyperglycemia characteristic of db/db mice for example? It would help determine the potential role of TAZ in pathophysiology.
Why do the authors not consider - and discuss - the possibility of regulation of glycogenolysis by TAZ-GR? The reduction in liver mass with TAZ knockdown seems more consistent with promoting glycogenolysis (as glycogen will take up more space/account for more liver mass than gluconeogenic precursors) vs gluconeogenesis.
The interpretation of the ITT is questionable: the authors state that there was no difference in insulin sensitivity, but if we calculate the plasma glucose concentrations during the ITT based on the time zero plasma glucose concentrations in the PTT, we would expect plasma glucose in the ITT to drop to ~60 mg/dl in the floxed mice and ~70 mg/dl in the L-TAZ KO animals. Given this degree of hypoglycemia, not only insulin sensitivity, but also hypoglycemia counterregulation (which involves glucocorticoids!) would modulate plasma glucose. Please discuss.
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