Alternative polyadenylation mediated the downregulation of lysophosphatidylglycerol acyltransferase 1 in metabolic dysfunction-associated steatotic liver disease

BACKGROUND: Alternative polyadenylation (APA) is a critical post-transcriptional regulatory mechanism involved in various diseases. Studies have shown dysfunction of APA-regulating factors such as SRSF10 in metabolic dysfunction-associated steatotic liver disease (MASLD). However, the downstream target genes and functional consequences remain unclear. This study investigated the role of APA in modulating LPGAT1 expression in MASLD. METHODS: Integrative analyses of bulk and single-cell RNA sequencing data from human and mouse MASLD livers were performed to identify APA changes. Functional validations were conducted using lysophosphatidylglycerol acyltransferase 1 (LPGAT1) 3’ UTR (3’ untranslated region)-knockout HepG2 cells under free fatty acid (FFA) treatment. RESULTS: Early hepatocyte-specific APA remodeling characterized by 3’ lengthening of metabolism-related genes, especially LPGAT1, was observed in MASLD. Despite elevated LPGAT1 mRNA levels, protein levels were suppressed in MASLD, associated with an increased usage of a proximal 3’ UTR segment enriched with miRNA binding sites. Deletion of this proximal region in HepG2 cells restored LPGAT1 protein levels and mitigated lipid accumulation under FFA exposure. CONCLUSIONS: This study establishes a cell type-resolved APA regulatory map for the MASLD liver and identifies APA-mediated repression of LPGAT1 as a critical driver of hepatic lipid accumulation. These findings highlight APA regulation as not only a pathogenic mechanism but also a promising molecular target for therapeutic interventions aimed at combating the progression of metabolic liver disease.