NFE2 Induces miR-423-5p to Promote Gluconeogenesis and Hyperglycemia by Repressing the Hepatic FAM3A-ATP-Akt Pathway

• Published in: Diabetes (New York, N.Y.) Vol. 66; no. 7; pp. 1819 - 1832
• Main Authors: Yang, Weili, Wang, Junpei, Chen, Zhenzhen, Chen, Ji, Meng, Yuhong, Chen, Liming, Chang, Yongsheng, Geng, Bin, Sun, Libo, Dou, Lin, Li, Jian, Guan, Youfei, Cui, Qinghua, Yang, Jichun
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.07.2017
• Subjects: Adenosine Triphosphate - metabolism; Adult; AKT protein; Animals; Case-Control Studies; Cytokines - genetics; Cytokines - metabolism; Diabetes mellitus; Fatty liver; Female; Gene expression; Gene Knock-In Techniques; Gene Knockdown Techniques; Gluconeogenesis; Gluconeogenesis - genetics; Glucose; Glucose metabolism; Glucose Tolerance Test; HEK293 Cells; Hep G2 Cells; Hepatocytes; Hepatocytes - metabolism; Humans; Hyperglycemia; Hyperglycemia - genetics; Hyperglycemia - metabolism; Insulin; Lipid metabolism; Lipids; Lipolysis; Liver - metabolism; Liver diseases; Male; Metabolism; Mice; MicroRNAs - genetics; Middle Aged; NF-E2 Transcription Factor, p45 Subunit - genetics; NF-E2 Transcription Factor, p45 Subunit - metabolism; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Obesity; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Signal Transduction
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db16-1172

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.