The pre-mRNA alternative splicing regulated by SRPK2: A new player in alcohol-associated liver disease?

Yang, Zong-Xiao; Ding, Wen–Xing

doi:10.1097/hep.0000000000000455

Hepatology

2023

DOI: 10.1097/hep.0000000000000455

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The pre-mRNA alternative splicing regulated by SRPK2: A new player in alcohol-associated liver disease?

Zong-Xiao Yang

Wen–Xing Ding

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2024

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LncRNA H19 promoted alcohol-associated liver disease through dysregulation of alternative splicing and methionine metabolism

Yang,

Jiang,

et al. 2024

Hepatology

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Long non-coding RNAs (lncRNAs) constitute a significant portion of the human genome. Among these, lncRNA H19, initially identified for its high expression during fetal development followed by a decline in the liver postnatally, re-emerges in various liver diseases. However, its specific role in alcohol-associated liver disease (ALD) remains unclear. Elevated H19 levels were detected in peripheral blood and livers of patients with alcohol-associated cirrhosis and hepatitis, as well as in livers of ethanol-fed mice. Hepatic overexpression of H19 exacerbated ethanol-induced liver steatosis and injury. Metabolomics analysis revealed decreased methionine levels in H19-overexpressed mouse livers, attributable to H19-mediated inhibition of Betaine-homocysteine methyltransferase (BHMT), a crucial enzyme in methionine synthesis. H19 regulated BHMT alternative splicing through Polypyrimidine tract-binding protein 1 (PTBP1), resulting in reduced Bhmt protein-coding variant. Maternally specific knockout of H19 (H19 Mat+/- ) or liver-specific knockout of the H19 differentially methylated domain (H19DMD Hep-/- ) in ethanol-fed mice upregulated BHMT expression and ameliorated hepatic steatosis. Furthermore, BHMT restoration counteracted H19-induced ethanol-mediated hepatic steatosis. This study identifies a novel mechanism whereby H19, via PTBP1-mediated BHMT regulation, influences methionine metabolism in ALD. Targeting the H19-PTBP1-BHMT pathway may offer new therapeutic avenues for ALD.

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LncRNA H19 promoted alcohol-associated liver disease through dysregulation of alternative splicing and methionine metabolism

Yang,

Jiang,

et al. 2024

Hepatology

View full text Add to dashboard Cite

show abstract

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The pre-mRNA alternative splicing regulated by SRPK2: A new player in alcohol-associated liver disease?

Cited by 1 publication

References 9 publications

LncRNA H19 promoted alcohol-associated liver disease through dysregulation of alternative splicing and methionine metabolism

LncRNA H19 promoted alcohol-associated liver disease through dysregulation of alternative splicing and methionine metabolism

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