lncRNA TUG1 mediates palmitic acid-induced neuronal lipotoxic injury via the miR-449a-5p/caspase-3 and Akt/GSK-3β axes

Abstract

A close relationship exists between excessive lipids and structural and functional brain dysfunction, with the long non-coding (lncRNA)-microRNA (miR)-mRNA network having an emerging role. Given the increasingly recognized role of the lncRNA taurine upregulated gene 1 (TUG1) in metabolic and neurodegenerative diseases, the present study investigated its function and mechanism in palmitic acid (PA)-induced neuronal injury. Results showed that lncRNA TUG1 expression was elevated in PA-treated HT-22 and SH-SY5Y cells. Moreover, cell-based in vitro detection including reverse transcription-quantitative polymerase chain reaction, western blotting and lactate dehydrogenase cytotoxicity assays demonstrated a positive association between lncRNA TUG1 expression and lactate dehydrogenase release and cleaved caspase-3 levels, whereas a negative association was observed with the expression levels of Bcl-2 and synaptic proteins (synapsin-1, synaptotagmin-1 and brain-derived neurotrophic factor) and the ratios of phosphorylated (p-) Akt/Akt and p-GSK-3β/GSK-3β. The downregulation of lncRNA TUG1 reversed PA-induced damage in HT-22 cells. Bioinformatics and dual-luciferase assays identified miR-449a-5p as the direct target of lncRNA TUG1. Rescue experiments revealed that miR-449a-5p mediated the effects of lncRNA TUG1 by targeting caspase-3 via the Akt/GSK-3β pathway. Collectively, these findings establish a causal axis in which lncRNA TUG1 derepresses caspase-3 and suppresses Akt/GSK-3β signaling by sponging miR-449a-5p, thereby driving neuronal lipotoxic injury.