Disrupted minor intron splicing activates reductive carboxylation-mediated lipogenesis to drive metabolic dysfunction-associated steatotic liver disease progression.

ABSTRACT: Aberrant RNA splicing is tightly linked to diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, we revealed that minor intron splicing, a unique and conserved RNA processing event, is largely disrupted upon the progression of metabolic dysfunction-associated steatohepatitis (MASH) in mice and humans. We demonstrated that deficiency of minor intron splicing in the liver induced MASH transition upon obesity-induced insulin resistance and LXR activation. Mechanistically, inactivation of minor intron splicing led to minor intron retention of Insig1 and Insig2, resulting in premature termination of translation, which drove proteolytic activation of SREBP1c. This mechanism was conserved in patients with MASH. Notably, disrupted minor intron splicin

SUBMITTER: Fu Y 

PROVIDER: S-EPMC12077890 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature