PDF(Pubmed)
Abstract：
OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) involves hepatic accumulation of intracellular lipid droplets via incompletely understood processes. Here, we report distinct and cooperative NAFLD roles of LysTTT-5\'tRF transfer RNA fragments and microRNA miR-194-5p.
METHODS: Combined use of diet induced obese mice with human-derived oleic acid-exposed Hep G2 cells revealed new NAFLD roles of LysTTT-5\'tRF and miR-194-5p.
RESULTS: Unlike lean animals, dietary-induced NAFLD mice showed concurrent hepatic decrease of both LysTTT-5\'tRF and miR-194-5p levels, which were restored following miR-132 antisense oligonucleotide treatment which suppresses hepatic steatosis. Moreover, exposing human-derived Hep G2 cells to oleic acid for 7 days co-suppressed miR-194-5p and LysTTT-5\'tRF levels while increasing lipid accumulation. Inversely, transfecting fattened cells with a synthetic LysTTT-5\'tRF mimic elevated mRNA levels of the metabolic regulator β-Klotho while decreasing triglyceride amounts by 30% within 24 h. In contradistinction, antisense suppression of miR-194-5p induced accumulation of its novel target, the NAFLD-implicated lipid droplet-coating PLIN2 protein. Further, two out of 15 steatosis-alleviating screened drug-repurposing compounds, Danazol and Latanoprost, elevated miR-194-5p or LysTTT-5\'tRF levels.
CONCLUSIONS: Our findings highlight the different yet complementary roles of miR-194-5p and LysTTT-5\'tRF and offer new insights into the complex roles of small non-coding RNAs and the multiple pathways involved in NAFLD pathogenesis.
METHODS: Combined use of diet induced obese mice with human-derived oleic acid-exposed Hep G2 cells revealed new NAFLD roles of LysTTT-5\'tRF and miR-194-5p.
RESULTS: Unlike lean animals, dietary-induced NAFLD mice showed concurrent hepatic decrease of both LysTTT-5\'tRF and miR-194-5p levels, which were restored following miR-132 antisense oligonucleotide treatment which suppresses hepatic steatosis. Moreover, exposing human-derived Hep G2 cells to oleic acid for 7 days co-suppressed miR-194-5p and LysTTT-5\'tRF levels while increasing lipid accumulation. Inversely, transfecting fattened cells with a synthetic LysTTT-5\'tRF mimic elevated mRNA levels of the metabolic regulator β-Klotho while decreasing triglyceride amounts by 30% within 24 h. In contradistinction, antisense suppression of miR-194-5p induced accumulation of its novel target, the NAFLD-implicated lipid droplet-coating PLIN2 protein. Further, two out of 15 steatosis-alleviating screened drug-repurposing compounds, Danazol and Latanoprost, elevated miR-194-5p or LysTTT-5\'tRF levels.
CONCLUSIONS: Our findings highlight the different yet complementary roles of miR-194-5p and LysTTT-5\'tRF and offer new insights into the complex roles of small non-coding RNAs and the multiple pathways involved in NAFLD pathogenesis.
摘要：
非酒精性脂肪性肝病（NAFLD）通过不完全了解的过程涉及细胞内脂滴的肝脏积累。这里,我们报道了LysTTT-5\'tRF转移RNA片段和microRNAmiR-194-5p的不同和协同NAFLD作用。与瘦肉动物不同，饮食诱导的NAFLD小鼠显示LysTTT-5'tRF和miR-194-5p水平的同时肝脏降低，在抑制肝脏脂肪变性的miR-132反义寡核苷酸治疗后恢复。此外，将人源HepG2细胞暴露于油酸7天共同抑制miR-194-5p和LysTTT-5\'tRF水平，同时增加脂质积累。相反，用合成的LysTTT-5\'tRF模拟物转染育肥细胞可提高代谢调节剂β-Klotho的mRNA水平，同时在24小时内将甘油三酯含量降低30％。相反，反义抑制miR-194-5p诱导其新靶点的积累，与NAFLD相关的脂质液滴包被PLIN2蛋白。Further,15种减轻脂肪变性的筛选药物再利用化合物中的两种，达那唑和拉坦前列素,miR-194-5p或LysTTT-5\'tRF水平升高。miR-194-5p和LysTTT-5'tRF的不同但互补的作用为非编码小RNA的复杂作用和涉及NAFLD发病机制的多个途径提供了新的见解。
