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

Under obese condition, hepatic FAM3A expression is repressed, 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 NAFLD patients with decreased FAM3A expression. miR-423-5p directly targeted FAM3A mRNA to repress its expression and 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 FAM3A-ATP-Akt pathway, and repressed gluconeogenic and lipogenic gene expression in diabetic mouse livers. miR-423 precursor gene was further shown to be a target gene of NFE2, which induced miR-423-5p expression to repress FAM3A-ATP-Akt pathway in cultured hepatocytes. Hepatic NFE2 overexpression upregulated miR-423-5p to repress FAM3A-ATP-Akt pathway, promoting gluconeogenesis and lipid deposition, and causing hyperglycemia in normal mice. In conclusion: under obese condition, activation of hepatic NFE2/miR-423-5p axis plays important roles in the progression of type 2 diabetes and NAFLD by repressing FAM3A-ATP-Akt signaling pathway.