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Background <p>Alternative polyadenylation (APA) is a critical post-transcriptional regulatory mechanism involved in various diseases. Studies have shown dysfunction of APA-regulating factors such as <i>SRSF10</i> 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 <i>LPGAT1</i> expression in MASLD.</p> Methods <p>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 <i>lysophosphatidylglycerol acyltransferase 1</i> (<i>LPGAT1</i>) 3’ UTR (3’ untranslated region)-knockout HepG2 cells under free fatty acid (FFA) treatment.</p> Results <p>Early hepatocyte-specific APA remodeling characterized by 3’ lengthening of metabolism-related genes, especially <i>LPGAT1</i>, was observed in MASLD. Despite elevated <i>LPGAT1</i> 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.</p> Conclusions <p>This study establishes a cell type-resolved APA regulatory map for the MASLD liver and identifies APA-mediated repression of <i>LPGAT1</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月8日

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  • Wei Feng,
  • Yuxin Liu,
  • Yunxiao Zhang,
  • Aowen Tian,
  • Miaoran Zhang,
  • Peng Xu,
  • Chang Shu,
  • Jianping Wen,
  • Jianli Yang,
  • Baiyu Qi,
  • Wenjin Qiu,
  • Zhengwen An,
  • Peng Chen

摘要

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.