LncRNA-Snhg3 Aggravates Hepatic Steatosis by Regulating PPARγ via SND1/H3K27me3

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 Snhg3 in the development and progression of MASLD, along with the underlying mechanisms. In vitro and in vivo experiments revealed that Snhg3 is involved in lipid metabolism and steatosis. The result showed that Snhg3 was significantly downregulated in the liver of high-fat-induced obesity (DIO) mice. Notably, palmitic acid promoted the expression of Snhg3 and overexpression of Snhg3 increased lipid accumulation in primary hepatocytes. Furthermore, knock-in and knock-out models showed significant changes in body and liver weight, heat production, total oxygen consumption, and carbon dioxide production. Hepatocyte-specific Snhg3 deficiency alleviated hepatic steatosis in DIO mice, whereas overexpression induced the opposite effect. Mechanistically, Snhg3 promoted the expression, stability and nuclear localization of SND1 protein via interacting with SND1, thereby inducing K63-linked ubiquitination modification of SND1. Moreover, Snhg3 decreased the H3K27me3 level and induced SND1-mediated chromatin loose remodeling, thus reducing H3K27me3 enrichment at the Pparγ promoter and enhancing Pparγ expression. In addition, the administration of PPARγ inhibitor T0070907 improved Snhg3 -aggravated hepatic steatosis. Our study revealed a new signaling pathway, Snhg3 /SND1/H3K27me3/PPARγ, responsible for MASLD and indicates that lncRNA-mediated epigenetic modification has a crucial role in the pathology of MASLD.