Loss of SNORA73 reprograms cellular metabolism and protects against steatohepatitis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA742760 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15010073_1.fastq.gz | Fastqsanger.gz | |||
| SRR15010073_2.fastq.gz | Fastqsanger.gz | |||
| SRR15010074_1.fastq.gz | Fastqsanger.gz | |||
| SRR15010074_2.fastq.gz | Fastqsanger.gz | |||
| SRR15010075_1.fastq.gz | Fastqsanger.gz |
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Project description:Dyslipidemia and resulting lipotoxicity are pathologic signatures of metabolic syndrome and type 2 diabetes. Excess lipid causes cell dysfunction and induces cell death through pleiotropic mechanisms that link to oxidative stress. However, pathways that regulate the response to metabolic stress are not well understood. Herein, we show that disruption of the box H/ACA SNORA73 small nucleolar RNAs encoded within the small nucleolar RNA hosting gene 3 (Snhg3) causes resistance to lipid-induced cell death and general oxidative stress in cultured cells. This protection from metabolic stress is associated with broad reprogramming of oxidative metabolism that is dependent on the mammalian target of rapamycin signaling axis. Furthermore, we show that knockdown of SNORA73 in vivo protects against hepatic steatosis and lipid-induced oxidative stress and inflammation. Our findings demonstrate a role for SNORA73 in the regulation of metabolism and lipotoxicity.
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Project description:Dyslipidemia and resulting lipotoxicity are pathologic signatures of metabolic syndrome and type 2 diabetes. Excess lipid causes cell dysfunction and induces cell death through pleiotropic mechanisms that link to oxidative stress. However, pathways that regulate the response to metabolic stress are not well understood. Herein, we show that disruption of the box H/ACA SNORA73 small nucleolar RNAs encoded within the small nucleolar RNA hosting gene 3 (Snhg3) causes resistance to lipid-induced cell death and general oxidative stress in cultured cells. This protection from metabolic stress is associated with broad reprogramming of oxidative metabolism that is dependent on the mammalian target of rapamycin signaling axis. Furthermore, we show that knockdown of SNORA73 in vivo protects against hepatic steatosis and lipid-induced oxidative stress and inflammation. Our findings demonstrate a role for SNORA73 in the regulation of metabolism and lipotoxicity.
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Project description:Recent studies have highlighted the beneficial effect of resolvin D1 (RvD1), a DHA-derived specialized pro-resolving mediator, on metabolic dysfunction-associated steatohepatitis (MASH), but the underlying mechanisms are not well understood. Our study aims to determine the mechanism by which RvD1 protects against MASH progression. RvD1 was administrated to MASH mice, followed by bulk and single-cell RNA sequencing analysis. Primary cells including bone marrow-derived macrophages (BMDMs), Kupffer cells, T cells, and primary hepatocytes were isolated to study the effect of RvD1 on inflammation, cell death, and fibrosis regression genes. RvD1 administration improved MASH features including reducing inflammation, cell death, and liver fibrosis. Mechanistically, RvD1 reduced inflammation by suppressing the stat1-cxcl10 signaling pathway in macrophages and prevented cell death by alleviating ER stress-mediated apoptosis in hepatocytes. Moreover, RvD1 induced Mmp2 and decreased Acta2 expression in hepatic stellate cells (HSCs), and promoted Mmp9 and Mmp12 expression in macrophages, leading to fibrosis regression in MASH. RvD1 reduced stat1-mediated pro-inflammatory response, mitigated ER stress-induced apoptosis, and promotes MMP-mediated fibrosis regression in MASH. Thus, our study highlights the therapeutic potential of RvD1 for MASH.
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