LncRNA <i>Snhg3</i> aggravates hepatic steatosis via PPARγ signaling.

Abstract

LncRNAs are involved in modulating the individual risk and the severity of progression in metabolic dysfunction-associated fatty liver disease (MASLD), but their precise roles remain largely unknown. This study aimed to investigate the role of lncRNA <i>Snhg3</i> in the development and progression of MASLD, along with the underlying mechanisms. The result showed that <i>Snhg3</i> was significantly downregulated in the liver of high-fat diet-induced obesity (DIO) mice. Notably, palmitic acid promoted the expression of <i>Snhg3</i> and overexpression of <i>Snhg3</i> increased lipid accumulation in primary hepatocytes. Furthermore, hepatocyte-specific <i>Snhg3</i> deficiency decreased body and liver weight, alleviated hepatic steatosis and promoted hepatic fatty acid metabolism in DIO mice, whereas overexpression induced the opposite effect. Mechanistically, <i>Snhg3</i> promoted the expression, stability and nuclear localization of SND1 protein via interacting with SND1, thereby inducing K63-linked ubiquitination modification of SND1. Moreover, <i>Snhg3</i> decreased the H3K27me3 level and induced SND1-mediated chromatin loose remodeling, thus reducing H3K27me3 enrichment at the <i>Pparg</i> promoter and enhancing PPARγ expression. The administration of PPARγ antagonist T0070907 improved <i>Snhg3</i>-aggravated hepatic steatosis. Our study revealed a new signaling pathway, <i>Snhg3</i>/SND1/H3K27me3/PPARγ, responsible for mice MASLD and indicates that lncRNA-mediated epigenetic modification has a crucial role in the pathology of MASLD.