1. NFE2 Induces miR-423-5p to Promote Gluconeogenesis and Hyperglycemia by Repressing the Hepatic FAM3A-ATP-Akt Pathway.
- Author
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Weili Yang, Junpei Wang, Zhenzhen Chen, Ji Chen, Yuhong Meng, Liming Chen, Yongsheng Chang, Bin Geng, Libo Sun, Lin Dou, Jian Li, Youfei Guan, Qinghua Cui, Jichun Yang, Yang, Weili, Wang, Junpei, Chen, Zhenzhen, Chen, Ji, Meng, Yuhong, and Chen, Liming
- Subjects
HYPERGLYCEMIA ,GLUCONEOGENESIS ,GLUCOSE synthesis ,OBESITY ,LIPID metabolism ,GLUCOSE metabolism ,ADENOSINE triphosphate metabolism ,PROTEIN metabolism ,ANIMAL experimentation ,CELLULAR signal transduction ,CYTOKINES ,EPITHELIAL cells ,FATTY liver ,GENETIC disorders ,GENETIC techniques ,GLUCOSE tolerance tests ,LIPID metabolism disorders ,LIVER ,METABOLISM ,MICE ,POLYMERASE chain reaction ,PROTEINS ,RNA ,TRANSFERASES ,CASE-control method ,REVERSE transcriptase polymerase chain reaction - Abstract
Hepatic FAM3A expression is repressed under obese conditions, but the underlying mechanism remains unknown. This study determined the role and mechanism of miR-423-5p in hepatic glucose and lipid metabolism by repressing FAM3A expression. miR-423-5p expression was increased in the livers of obese diabetic mice and in patients with nonalcoholic fatty liver disease (NAFLD) with decreased FAM3A expression. miR-423-5p directly targeted FAM3A mRNA to repress its expression and the FAM3A-ATP-Akt pathway in cultured hepatocytes. Hepatic miR-423-5p inhibition suppressed gluconeogenesis and improved insulin resistance, hyperglycemia, and fatty liver in obese diabetic mice. In contrast, hepatic miR-423-5p overexpression promoted gluconeogenesis and hyperglycemia and increased lipid deposition in normal mice. miR-423-5p inhibition activated the FAM3A-ATP-Akt pathway and repressed gluconeogenic and lipogenic gene expression in diabetic mouse livers. The miR-423 precursor gene was further shown to be a target gene of NFE2, which induced miR-423-5p expression to repress the FAM3A-ATP-Akt pathway in cultured hepatocytes. Hepatic NFE2 overexpression upregulated miR-423-5p to repress the FAM3A-ATP-Akt pathway, promoting gluconeogenesis and lipid deposition and causing hyperglycemia in normal mice. In conclusion, under the obese condition, activation of the hepatic NFE2/miR-423-5p axis plays important roles in the progression of type 2 diabetes and NAFLD by repressing the FAM3A-ATP-Akt signaling pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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