Dexamethasone-induced Krüppel-like factor 9 expression promotes hepatic gluconeogenesis and hyperglycemia

Abstract

Chronic glucocorticoid therapy has serious side effects, including diabetes and fatty liver. However, the molecular mechanisms responsible for steroid-induced diabetes remain largely enigmatic. Here, we show that hepatic Krüppel-like factor 9 (Klf9) gene expression is induced by dexamethasone and fasting. The overexpression of Klf9 in primary hepatocytes strongly stimulated Pgc1a gene expression through direct binding to its promoter, thereby activating the gluconeogenic program. However, Klf9 mutation abolished the stimulatory effect of dexamethasone on cellular glucose output. Adenovirusmediated overexpression of KLF9 in the mouse liver markedly increased blood glucose levels and impaired glucose tolerance. Conversely, both global Klf9-mutant mice and liver-specific Klf9-deleted mice displayed fasting hypoglycemia. Moreover, the knockdown of Klf9 in the liver in diabetic mouse models, including ob/ob and db/db mice, markedly lowered fasting blood glucose levels. Notably, hepatic Klf9 deficiency in mice alleviated hyperglycemia induced by chronic dexamethasone treatment. These results suggest a critical role for KLF9 in the regulation of hepatic glucose metabolism and identify hepatic induction of KLF9 as a mechanism underlying glucocorticoid therapy-induced diabetes.

<p>Glucocorticoid-Induced Fatty Liver Disease</p>

“…[36][37][38] A recent study showed that glucocorticoids increase the expression of the transcription factor Krϋppel-like factor 9 (KLF9), which in turn augments the expression of PGC1α. 39 Deletion of the KLF9 gene abolished the stimulatory effect of glucocorticoids on glucose output. Hence, GC-induced stimulation of gluconeogenesis involves stimulation of the cascade of KLF9-PGC1α-GRU-containing genes.…”

Klf9 is a key feedforward regulator of the transcriptomic response to glucocorticoid receptor activity

“…We have found by ATAC-seq that the promoter region of klf9 is one of the most differentially open regions of chromatin in blood cells of adults derived from cortisol-treated embryos, possibly reflecting the chronically elevated cortisol levels maintained by those adults (Hartig et al, submitted). In mice klf9 was recently shown to mediate glucocorticoid-induced metabolic dysregulation in liver 20 . Our RNA-seq results from klf9 -/larvae ( Fig.…”

“…In the same study it was also shown that hippocampuses of women with major depression were found to overexpress KLF9 19 . Finally, it was recently discovered that Dexamethasone-induced upregulation of Klf9 promotes hepatic gluconeogenesis and hyperglycemia in mice 20 . Thus, klf9 is a GR target gene that dynamically controls GC signaling, and its overexpression is implicated in stress-induced pathology.…”

Taking KLF9 to “Cort” for crimes against metabolism

“…In this issue of the JCI, Cui and colleagues introduce a critical role of the transcription factor Krüppel-like factor 9 (KLF9) in linking GC signaling to gluco neogenesis (8). Through the use of gain-and loss-offunction experiments in hepatocytes and in multiple murine models, they establish that fasting-induced and exogenously administered GCs induce transcription of hepatic Klf9, which then augments Pgc1a and, ultimately, the transcription of gluconeogenic and lipid oxidation genes.…”