Dexamethasone-induced Kruppel-like factor 9 expression promotes hepatic gluconeogenesis and hyperglycemia
Dexamethasone-induced Kruppel-like factor 9 expression promotes hepatic gluconeogenesis and hyperglycemia
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地塞米松诱导的 Krüppel 样因子 9 表达促进肝糖异生和高血糖
DOI：
10.1172/jci66062
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发表时间：
2019-06-03
影响因子：
15.9
通讯作者：
Chang, Yongsheng
中科院分区：
文献类型：
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作者：
Cui, Anfang;Fan, Heng;Chang, Yongsheng
慢性糖皮质激素治疗有严重的副作用，包括糖尿病和脂肪肝。然而，激素性糖尿病的分子机制很大程度上仍是个谜。在这里，我们证明了肝脏Kruppel样因子9(KLF9)基因的表达是由地塞米松和禁食诱导的。KLF9在原代肝细胞中的过表达通过直接与其启动子结合，从而激活糖异生程序，从而强烈地刺激PGC1a基因的表达。然而，Klf9突变取消了地塞米松对细胞葡萄糖输出的刺激作用。腺病毒介导的KLF9在小鼠肝脏的过表达显著增加了血糖水平，并损害了糖耐量。相反，全局KLF9突变小鼠和肝脏特异性KLF9缺失小鼠都表现出空腹低血糖。此外，在包括ob/ob和db/db小鼠在内的糖尿病小鼠模型中，KLF9基因的敲除显著降低了空腹血糖水平。值得注意的是，小鼠肝脏KLF9缺乏减轻了慢性地塞米松治疗引起的高血糖。这些结果表明KLF9在调节肝脏葡萄糖代谢中起着关键作用，并确认肝脏对KLF9的诱导是糖皮质激素诱导糖尿病的一个机制。
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 Kruppel-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. Adenovirus-mediated 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.