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

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

PROVIDER: PRJNA1136453 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29842581_1.fastq.gz	Fastqsanger.gz
	SRR29842581_2.fastq.gz	Fastqsanger.gz
	SRR29842582_1.fastq.gz	Fastqsanger.gz
	SRR29842582_2.fastq.gz	Fastqsanger.gz
	SRR29842583_1.fastq.gz	Fastqsanger.gz

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

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

Disrupted Minor Intron Splicing Activates Reductive Carboxylation-mediated Lipogenesis to Drive MASH Progression

2025-04-23 | GSE252030 | GEO

Disrupted Minor Intron Splicing Activates Reductive Carboxylation-mediated Lipogenesis to Drive MASH Progression

Project description:Disrupted Minor Intron Splicing Activates Reductive Carboxylation-mediated Lipogenesis to Drive MASH Progression

| PRJNA1057141 | ENA

Reductive carboxylation epigenetically instructs effector T cell differentiation

Project description:Reductive carboxylation epigenetically instructs effector T cell differentiation

| PRJNA791337 | ENA

Reductive carboxylation epigenetically instructs effector T cell differentiation [ATAC-Seq]

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

Reductive carboxylation epigenetically instructs effector T cell differentiation [RNA-Seq]

2023-07-17 | GSE192395 | GEO

Reductive carboxylation epigenetically instructs effector T cell differentiation [RNA-Seq]

Project description:Reductive carboxylation epigenetically instructs effector T cell differentiation [RNA-Seq]

| PRJNA791335 | ENA

Reductive carboxylation epigenetically instructs effector T cell differentiation [ATAC-Seq]

Project description:Reductive carboxylation epigenetically instructs effector T cell differentiation [ATAC-Seq]

| PRJNA791336 | ENA

Reductive carboxylation epigenetically instructs effector T cell differentiation

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-07-17 | GSE192396 | GEO

ZBP1-mediated apoptosis and inflammation exacerbate steatotic liver ischemia/reperfusion injury

Project description:Abstract Background & Aims: In liver transplantation, steatotic donor livers are rapidly increasing but are more susceptible to ischemia-reperfusion (I/R) injury. This study aimed to investigate the underlying mechanisms and identify therapeutic targets. Methods: Cell death markers were determined in donor livers and animal models. Casp8f/f;Alb-Cre, Ripk1D138N/D138N, Tnf-/-, Ripk3-/-, Trif-/-, Zbp1-/- mice were fed high fat diet or choline-deficient high fat diet to induce steatotic livers and were then subjected to I/R injury to investigate the mechanisms of cell death and inflammation. Primary mouse or human hepatocytes were isolated and subjected to hypoxia-reoxygenation challenge to further elucidate the regulation mechanisms. Results: Apoptosis- and inflammation-induced injury was exacerbated in I/R process of steatotic livers, with inflammation-induced injury playing a more predominant role. In both normal and steatotic livers, caspase-8 ablation mitigated I/R injury by reducing apoptosis but not inflammation while RIPK1 kinase inhibition more effectively protected against I/R injury by alleviating both apoptosis and inflammation. Z-DNA binding protein 1 (ZBP1) but not TNF-α deficiency inhibited RIPK1 activation and protected against I/R injury in steatotic livers but not normal livers. In steatotic livers, overmuch palmitic acid triggered ZBP1 transcription through activating JNK pathway. During liver transplantation, excessive reactive oxygen species were generated during I/R injury and triggered ZBP1 oligomerization, which led to the kinase activation of RIPK1 and the subsequent aggravation of apoptosis- and inflammation-induced injury. Conclusions: ZBP1-mediated apoptosis and inflammation exacerbate steatotic liver I/R injury, which could be leveraged to protect steatotic donor livers in transplantation.

2024-06-01 | GSE254747 | GEO

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