<i>LncRNA Gm17586</i> Reduces HSCs Activation by Increasing SIRT1 Transcript Activity to Enhance Smad3 Deacetylation

<i>Long noncoding RNAs</i> (<i>lncRNAs</i>) play crucial roles in liver fibrosis (LF). We previously showed that the key <i>lncRNA Gm17586</i> is involved in LF, but its molecular mechanism remains unclear. Primary hepatic stellate cells (HSCs) were isolated from LF mice. Real-time quantitative PCR and Western blotting were used to detect the expression of <i>lncRNA Gm17586</i>, <i>Sirtuin 1</i> (<i>SIRT1</i>), and <i>Smad homolog 3</i> (<i>Smad3</i>). Cell counting kit-8 and flow cytometry were used to detect the cell viability and cell cycle of the HSCs. Finally, immunofluorescence (IF) and fluorescence <i>in situ</i> hybridization (FISH) were used to observe the cellular colocalization of <i>lncRNA Gm17586</i> and <i>SIRT1</i>. In HSCs from LF mice, the expression of the <i>lncRNA Gm17586</i> was significantly reduced and negatively correlated with the expression of the HSCs activation markers <i>α-smooth muscle actin</i> (<i>α-SMA</i>) and <i>collagen I</i>. Overexpression of the <i>lncRNA Gm17586</i> suppressed <i>α-SMA</i> and <i>collagen I</i> expression, as well as HSCs proliferation. Bioinformatics analysis and FISH experiments revealed that the <i>lncRNA Gm17586</i> has potential binding sites on <i>SIRT1</i> mRNA and shares a common subcellular localization. Notably, overexpression of the <i>lncRNA Gm17586</i> led to marked increases in <i>SIRT1</i> mRNA and protein levels. Further studies on the role of <i>SIRT1</i> as a deacetylase revealed that overexpression of <i>SIRT1</i> significantly reduced <i>Smad3</i> mRNA and protein levels. Importantly, <i>SIRT1</i> overexpression also markedly decreased <i>Smad3</i> protein acetylation, suggesting that a mechanism exists by which <i>Smad3</i> is regulated via deacetylation in HSCs. The results of this study suggested that downregulation of <i>lncRNA Gm17586</i> expression reduced the expression of <i>SIRT1</i>, leading to decreased <i>Smad3</i> deacetylation and promoting HSCs activation. The <i>lncRNA Gm17586</i> may be a novel therapeutic target for the diagnosis and treatment of LF.