Disrupted Minor Intron Splicing Activates Reductive Carboxylation-mediated Lipogenesis to Drive MASH Progression
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ABSTRACT:
PROVIDER: PRJNA1057141 | ENA |
REPOSITORIES: ENA
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Project description:Aberrant RNA splicing is tightly linked to diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). Here, 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 deficiency of minor intron splicing in the liver induces MASH transition upon obesity-induced insulin resistance and LXR activation. Mechanistically, inactivation of minor intron splicing leads to minor intron retention of Insig1 and Insig2, resulting in premature termination of translation, which drives proteolytic activation of SREBP1c. This mechanism is conserved in human patients with MASH. Notably, disrupted minor intron splicing activates glutamine reductive metabolism for de novo lipogenesis through the induction of Idh1, which causes the accumulation of ammonia in the liver, thereby initiating hepatic fibrosis upon LXR activation. Ammonia clearance or IDH1 inhibition blocks hepatic fibrogenesis and mitigates MASH progression. More importantly, the overexpression of Zrsr1 restored minor intron retention and ameliorated the development of MASH, indicating that dysfunctional minor intron splicing is an emerging pathogenic mechanism that drives MASH progression. Additionally, reductive carboxylation flux triggered by minor intron retention in hepatocytes serves as a crucial checkpoint and potential target for MASH therapy.
2025-04-23 | GSE252030 | GEO
Project description:Aberrant RNA splicing is tightly linked to diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). Here, 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 deficiency of minor intron splicing in the liver induces MASH transition upon obesity-induced insulin resistance and LXR activation. Mechanistically, inactivation of minor intron splicing leads to minor intron retention of Insig1 and Insig2, resulting in premature termination of translation, which drives proteolytic activation of SREBP1c. This mechanism is conserved in human patients with MASH. Notably, disrupted minor intron splicing activates glutamine reductive metabolism for de novo lipogenesis through the induction of Idh1, which causes the accumulation of ammonia in the liver, thereby initiating hepatic fibrosis upon LXR activation. Ammonia clearance or IDH1 inhibition blocks hepatic fibrogenesis and mitigates MASH progression. More importantly, the overexpression of Zrsr1 restored minor intron retention and ameliorated the development of MASH, indicating that dysfunctional minor intron splicing is an emerging pathogenic mechanism that drives MASH progression. Additionally, reductive carboxylation flux triggered by minor intron retention in hepatocytes serves as a crucial checkpoint and potential target for MASH therapy.
2025-04-01 | GSE272322 | GEO
Project description:Disrupted minor intron splicing activates reductive carboxylation-mediated lipogenesis to drive metabolic dysfunction–associated steatotic liver disease progression
| PRJNA1136453 | ENA
Project description:Reductive carboxylation epigenetically instructs effector T cell differentiation
| PRJNA791337 | ENA
Project description:The differentiation into effector and memory CD8+ T cell subsets was recently associated with specific metabolic pathways to sustain their diverse bioenergetics needs. Clonally expanding T cells rely strongly on glucose and glutamine utilization to maintain high cell proliferation and effector functions. We found that proliferating effector CD8+ T cells, in addition to oxidizing, also reductively carboxylate glutamine, to maintain rapid lipid synthesis for cell proliferation. Interfering with reductive carboxylation by genetic deletion of isocitrate dehydrogenase 2 (IDH2), the enzyme mediating this reaction in the mitochondria, surprisingly did not impair proliferation and effector function upon infection, but skewed the CD8+ T cell response towards enhanced memory differentiation. Pharmacological IDH2 inhibition during in vitro CAR T cell manufacturing also induced memory features and thus strongly enhanced their antitumor activity and persistence upon adoptive cell transfer into murine melanoma tumour models. Mechanistically, IDH2 inhibition caused a disequilibrium in metabolites regulating histone-modifying enzymes, which altered the epigenetic landscape, increasing chromatin accessibility at genes required for memory differentiation. Restoring this metabolite balance or preventing the epigenetic modifications abrogated the enhanced CD8+ T cell memory differentiation and anti-tumour activity induced by IDH2 inhibition. These findings suggest that reductive carboxylation of glutamine in activated CD8+ T cells is dispensable for their effector function, but instead primarily instructs a metabolite composition that epigenetically locks them in a terminal effector differentiation program. Blocking this metabolic route allows for increased memory formation, which can be exploited to optimize CAR T cell production for adoptive cell transfer immunotherapy against cancer.
2023-07-17 | GSE192395 | GEO
Project description:The differentiation into effector and memory CD8+ T cell subsets was recently associated with specific metabolic pathways to sustain their diverse bioenergetics needs. Clonally expanding T cells rely strongly on glucose and glutamine utilization to maintain high cell proliferation and effector functions. We found that proliferating effector CD8+ T cells, in addition to oxidizing, also reductively carboxylate glutamine, to maintain rapid lipid synthesis for cell proliferation. Interfering with reductive carboxylation by genetic deletion of isocitrate dehydrogenase 2 (IDH2), the enzyme mediating this reaction in the mitochondria, surprisingly did not impair proliferation and effector function upon infection, but skewed the CD8+ T cell response towards enhanced memory differentiation. Pharmacological IDH2 inhibition during in vitro CAR T cell manufacturing also induced memory features and thus strongly enhanced their antitumor activity and persistence upon adoptive cell transfer into murine melanoma tumour models. Mechanistically, IDH2 inhibition caused a disequilibrium in metabolites regulating histone-modifying enzymes, which altered the epigenetic landscape, increasing chromatin accessibility at genes required for memory differentiation. Restoring this metabolite balance or preventing the epigenetic modifications abrogated the enhanced CD8+ T cell memory differentiation and anti-tumour activity induced by IDH2 inhibition. These findings suggest that reductive carboxylation of glutamine in activated CD8+ T cells is dispensable for their effector function, but instead primarily instructs a metabolite composition that epigenetically locks them in a terminal effector differentiation program. Blocking this metabolic route allows for increased memory formation, which can be exploited to optimize CAR T cell production for adoptive cell transfer immunotherapy against cancer.
2023-07-17 | GSE192394 | GEO
Project description:Reductive carboxylation epigenetically instructs effector T cell differentiation [ATAC-Seq]
| PRJNA791336 | ENA
Project description:Reductive carboxylation epigenetically instructs effector T cell differentiation [RNA-Seq]
| PRJNA791335 | ENA
Project description:Rates of hepatocellular carcinoma (HCC) are increasing rapidly due to the epidemic of metabolic dysfunction-associated steatohepatitis (MASH). In addition to increased incidence, emerging evidence suggests that MASH driven HCC is associated with poor survival outcomes potentially due to the complex liver microenvironment which is characterized by hypoxia, steatosis, and fibrosis. Lenvatinib, is a multi-tyrosine kinase inhibitor, that is a standard of care therapy for unresected HCC, but 5-year survival rates are less than 20%. Therefore, developing treatments that inhibit cancer growth kinetics and target the tumor microenvironment to improve the therapeutic response in MASH-HCC are needed. Salsalate is a rheumatoid arthritis therapy that stimulates the AMP-activated protein kinase (AMPK) increasing fatty acid oxidation while reducing de-novo lipogenesis, fibrosis and cell proliferation pathways. Thus, we hypothesized that Salsalate could improve the therapeutic efficacy of Lenvatinib in MASH-HCC. In the current study, we show that treatment of human HCC cells with clinically relevant concentrations of Lenvatinib and Salsalate synergistically suppress proliferation and clonogenic survival, activate AMPK and inhibit the mTOR-HIF1a and Erk1/2 signaling pathways. In orthotopic xenograft and MASH-HCC mouse models Lenvatinib and Salsalate combination therapy suppressed angiogenesis and steatosis and fibrosis. RNA-sequencing revealed combination therapy enhanced mitochondria fatty acid oxidation and suppressed glycolysis, angiogenesis, fibrosis and cell cycle progression with regulatory network analysis suggesting a potential role for Activating transcription factor 3 (ATF3) and ETS-proto-oncogene-1 (ETS1). These data suggest that Lenvatinib and Salsalate combination therapy may have therapeutic potential for MASH-HCC due to effective metabolic rewiring and growth inhibition, leading to improvements in the liver microenvironment and inhibition of HCC proliferation.
2025-02-01 | GSE282660 | GEO
Project description:Excess cholesterol accumulation contributes to fibrogenesis in metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis [NASH]), but how hepatic cholesterol metabolism becomes dysregulated in MASH is not completely understood. We show here that human fibrotic MASH livers have decreased EHBP1, a novel GWAS locus associated with LDL cholesterol, and that the EHBP1 rs10496099 T>C variant in MASH patients is associated with decreased hepatic EHBP1 expression and with augmented MASH fibrosis. Congruent with the human data, EHBP1 loss- and gain-of-function increases and decreases MASH fibrosis in mice, respectively. Mechanistic studies reveal that EHBP1 promotes sortilin (SORT1)-mediated PCSK9 secretion, leading to LDLR degradation, decreased LDL uptake, and reduced TAZ, a fibrogenic effector. At a cellular level, EHBP1 deficiency affects intracellular localization of retromer, a protein complex required for sortilin stabilization. Our novel therapeutic approach to stabilizing retromer is effective in mitigating MASH fibrosis. Moreover, we show that the TNFα/PPARα pathway suppresses EHBP1 in MASH. These data not only provide new mechanistic insight into the role of EHBP1 in cholesterol metabolism and MASH fibrosis by uncovering the interaction between EHBP1 and other cholesterol-related loci, including SORT1, PCSK9, and LDLR, but also elucidate a novel interplay between inflammation and EHBP1-mediated cholesterol metabolism.
2025-01-23 | GSE232780 | GEO