Dexamethasone-induced Krüppel-like factor 9 expression promotes hepatic gluconeogenesis and hyperglycemia release_u4wzdicv7zdqnehsbrl23an7ba

by Anfang Cui, Heng Fan, Yinliang Zhang, Yujie Zhang, Dong Niu, Shuainan Liu, Quan Liu, Wei Ma, Zhufang Shen, Lian Shen, Yanling Liu, Huabing Zhang (+8 others)

Published in Journal of Clinical Investigation by American Society for Clinical Investigation.

Volume 129, Issue 6 p2266-2278 (2019)


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. 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.
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Type  article-journal
Stage   published
Date   2019-04-29
Language   en ?
DOI  10.1172/jci66062
PubMed  31033478
PMC  PMC6546458
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ISSN-L:  0021-9738
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