Journal Article

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

Shen, Lian, Xue, Yuan, Liu, Yanling, Zhang, Yinliang, Fang, Fude, Shen, Zhufang, Cui, Qinghua, Yang, Jichun, Cui, Anfang, Fan, Heng, Chang, Yongsheng, Zhang, Yujie, Liu, Shuainan, Ma, Wei, Xiao, Xinhua, Niu, Dong, Cui, Ying, Wang, Qinghua, Liu, Quan, Zhang, Huabing

2019

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Adenoviridae / Adenoviruses / Animal models / Animals / Binding sites / Biochemistry / Biomedical research / Blood glucose / Central nervous system depressants / Dexamethasone / Dexamethasone - adverse effects / Dexamethasone - pharmacology / Diabetes / Diabetes mellitus / Diabetes Mellitus, Experimental - chemically induced / Diabetes Mellitus, Experimental - genetics / Diabetes Mellitus, Experimental - metabolism / Diabetes Mellitus, Experimental - pathology / Diabetes therapy / Fasting / Fatty liver / Gene expression / Gene Expression Regulation - drug effects / Genes / Glucocorticoids / Gluconeogenesis / Gluconeogenesis - drug effects / Gluconeogenesis - genetics / Glucose / Glucose metabolism / Glucose tolerance / Hepatocytes / Hepatocytes - metabolism / Hepatocytes - pathology / Homeostasis / Hyperglycemia / Hyperglycemia - chemically induced / Hyperglycemia - genetics / Hyperglycemia - metabolism / Hyperglycemia - pathology / Hypertension / Hypoglycemia / Insulin resistance / Kruppel-Like Transcription Factors - biosynthesis / Kruppel-Like Transcription Factors - genetics / Liver / Liver - metabolism / Liver - pathology / Liver diseases / Metabolism / Mice / Mice, Knockout / Molecular modelling / Oxidative stress / Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics / Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism / Physiology / Proteins / Steroids / Steroids (Organic compounds) / Transcription factors / Transduction, Genetic