Aging Promotes Metabolic Dysfunction-Associated Steatotic Liver Disease by Inducing Ferroptotic Stress
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ABSTRACT:
PROVIDER: PRJNA1094958 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28516855.fastq.gz | Fastqsanger.gz | |||
| SRR28516856.fastq.gz | Fastqsanger.gz | |||
| SRR28516857.fastq.gz | Fastqsanger.gz | |||
| SRR28516858.fastq.gz | Fastqsanger.gz | |||
| SRR28516859.fastq.gz | Fastqsanger.gz |
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Project description:Aging Promotes Metabolic Dysfunction-associated Steatotic Liver Disease and Multi-Organ Dysfunction by Inducing Ferroptotic Stress
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Project description:Aging is an inevitable consequence of living that undermines cellular resiliency to cause tissue degeneration and eventual multi-organ dysfunction. Susceptibility to biological consequences of aging varies among organs and individuals. Stressors that challenge resiliency unmask these differences. Hence, aging increases the risk for failure of many metabolically-stressed organs and exacerbates liver degeneration related to obesity and diabetes. We discovered that aging promotes ferroptosis, a type of metabolism-regulated cell death, in hepatocytes. Hepatocytes that have launched the ferroptotic death program adapt their metabolism to survive but become damaged and dysfunctional. Metabolic stressors amplify this, increasing the burden of ferroptosis-adapted cells and liver damage. Blocking ferroptotic signaling in old livers reduces accumulation of adapted hepatocytes and reverts livers to a more youthful resilient state despite exogenous stressors. Ferroptosis is also induced in other organs that are damaged by chronic metabolic stress, identifying ferroptosis as a tractable conserved mechanism for aging-related multi-organ dysfunction.
2024-07-01 | GSE262457 | GEO
Project description:Aging increases the risk for failure of many metabolically-stressed organs and exacerbates liver degeneration related to obesity and diabetes. We used snRNA-seq to identify the effect of metabolic disease (MASLD) on biological aging of hepatocyte.
2024-07-02 | GSE262939 | GEO
Project description:Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. While ferroptosis has been identified as a mechanism for suppressing cancer, its overall physiological significance remains poorly understood. Recent studies have revealed that labile iron and lipid peroxides are released from ferroptotic cells, leading to the propagation of ferroptosis through lipid peroxidation. However, other specific effects of secreted factors derived from ferroptotic cells remain unclear. We constructed a model cell system capable of inducing ferroptosis by re-expressing the transcription factor BACH1, a potent inducer of ferroptosis, in immortalized mouse embryonic fibroblasts (iMEFs). We investigated the impact of the secreted factors from ferroptotic cells with the iMEFs. As a result, we observed that the administration of supernatant media from ferroptotic iMEFs activated proliferation of hepatoma cells and suppressed cellular senescence-like features. This suggested that ferroptotic MEFs secrete anti-senescent substances. Transcriptome analysis of ferroptotic MEFs revealed an increase in the secretion of longevity factor FGF21 in a BACH1-dependent manner. Furthermore, the anti-senescent effects of the supernatant media from these ferroptotic cells were canceled by the knockout of Fgf21. Totally, it is suggested that BACH1 promotes ferroptosis in fibroblasts and contributes to the suppression of cellular senescence in neighboring cells by inducing FGF21 secretion from fibroblasts. It was also discovered that BACH1 not only activates indirectly the transcription of FGF21 by enhancing ferroptotic stress but also increases FGF21 protein level by suppressing the selective autophagic degradation of FGF21 through the transcriptional repression for Sqstm1 and Lamp2a. This represents a dual mechanism of FGF21 upregulation mediated by BACH1, suggesting that BACH1 is a potent inducer of FGF21 expression. It was also found that the BACH1-ferroptosis-FGF21 axis can suppress obesity of mice under high fat diet or short lifespan of progeria mice, closely associated phenotypes with aging. The inhibition of these aging-related phenotypes is considered to be a novel physiological significance of ferroptosis, and BACH1 is considered to function as a longevity gene by promoting ferroptotsis and subsequent FGF21 expression.
2024-06-11 | GSE238147 | GEO
Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a multi-organ damage that includes hepatic dysfunction, which has been observed in over 50% of COVID-19 patients. Liver injury in COVID-19 patients could be attributed to the cytopathic effects induced by the interation between the virus and hepatic cells, exacerbated immune responses or treatment-associated drug toxicity. Here we demonstrate that primary hepatocytes are susceptible to infection in different models: hepatocytes derived from humanized angiotensin-converting enzyme-2 (hACE-2) mice and THLE-2 human cells. Pseudotyped viral particles engineered to express the full-length spike of SARS-CoV-2 and recombinant RBD bind to ACE2 expressed by hepatocytes, promoting metabolic reprogramming towards glycolysis but also mitochondrial dysfunction. In the context of non-alcoholic steatohepatitis (NASH), steatotic hepatocytes derived from hACE2 mice are more vulnerable to infection, as a result of increased expression of ACE2. Metformin, a common therapeutic option for hyperglycemia in type 2 diabetes (T2D) patients, prevents the interaction between the spike of SARS-CoV-2 and steatotic hepatocytes by reducing the expression of hACE2. In summary, we provide evidence that hepatocytes are amenable to SARS-CoV-2 infection and propose metformin as a therapeutic strategy to prevent liver dysfunction caused by SARS-CoV-2 in the context of NASH.
2022-10-14 | PXD035263 | Pride
Project description:A Mouse Model for Metabolic Dysfunction-associated Steatotic Liver Disease and Hepatocellular Carcinoma
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Project description:Background and aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) progresses from steatosis (Metabolic dysfunction-associated steatotic liver, MASL) to Metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis. Activation of Hepatic Stellate Cells (HSCs) into fibrogenic myofibroblasts plays a critical role in the pathogenesis of MASH liver fibrosis. Here we compared gene expression and chromatin accessibility profiles of human HSCs in NORMAL, MASL, and MASH livers at single cell resolution. Methods: 18 human livers were profiled using single-nucleus (sn) RNA-seq and snATAC-seq. High priority targets were identified and then tested in 2D human HSCs, 3D human liver spheroids, and HSC-specific gene knockout mice. Results: This study identified novel gene regulatory mechanisms underlying MASL- and MASH-associated HSC heterogeneity and outlined potential strategies for anti-fibrotic therapy. Specifically, MASH-enriched HSC-subcluster hA1, represented by highly fibrogenic population of myofibroblasts, served as a critical source of extracellular matrix protein (ECM) in MASH, and its activation was regulated via a cross-talk between lineage-specific (JUNB/AP1), cluster-specific (RUNX1/2) and signal-specific (FOXA1/2) transcription factors (TFs). Additionally, we identified a set of core genes (GAS7, SPON1, SERPINE1, LTBP2, KLF9, EFEMP1) that drive ECM production in hA1 HSCs. The pathological relevance of the selected hA1 targets, such as SERPINE1 and others, was demonstrated using siRNA-based HSC-specific gene knockdown or pharmacological inhibitor of SERPINE1 in 3D human MASH liver spheroids, and HSC-specific Serpine1 knockout mice with MASH. Conclusion: We identified potential targets for anti-fibrotic therapy of MASH in patients.
2024-11-13 | GSE244832 | GEO
Project description:The lack of an appropriate preclinical model of metabolic dysfunction-associated steatotic liver disease (MASLD) that recapitulates the whole disease spectrum impedes exploration of disease pathophysiology and the development of effective treatment strategies. Considering the fact that MASLD patients accompanying type 2 diabetes mellitus (T2DM) have high risk of developing metabolic dysfunction-associated steatohepatitis (MASH), advanced fibrosis, and HCC, we treated low-dose streptozotocin (STZ; 40 mg/kg) for 5 consecutive days and subsequently fed a high-fat diet (HFD) to male C57BL/6J mice at 7 weeks of age (STZ+HFD). STZ+HFD mice gradually developed fatty liver, MASH, hepatic fibrosis, and hepatocellular carcinoma (HCC) in the context of metabolic dysfunction. In particular, from 20 weeks of age, MASH was evident, and from 32 weeks of age, advanced fibrosis was developed. At 38 weeks, a proportion of STZ+HFD mice developed HCC, which was subsequently observed in all mice up to 68 weeks of age. Furthermore, the hepatic transcriptomic features of STZ+HFD mice closely reflected those of obese patients with T2DM, MASH and MASLD-related HCC. Notably, dietary changes and tirzepatide administration alleviated MASH, hepatic fibrosis, and hepatic tumorigenesis in STZ+HFD mice. In conclusion, a murine model recapitulating the main histopathologic, transcriptomic, and metabolic alterations observed in MASLD patients with metabolic dysfunction was successfully established.
2024-06-17 | GSE246221 | GEO
Project description:A gradual decline in renal function occurs even in healthy aging individuals. In addition to aging per se, concurrent metabolic syndrome and hypertension, which are common in the aging population, can induce mitochondrial dysfunction, and inflammation, which collectively contribute to age-related kidney disease. Here we studied the role of the nuclear hormone receptors, the estrogen related receptors (ERRs) in regulation of age-related mitochondrial dysfunction and inflammation. ERRs are decreased in aging human and mouse kidneys and preserved in aging mice with lifelong caloric restriction (CR). Our studies identified ERRs as important modulators of age-related mitochondrial dysfunction and inflammation. ERRα, ERRβ, and ERRγ levels are decreased in the aging kidney. Remarkably, only a 4-week treatment of 21-month-old mice with the pan ERR agonist reversed the age-related increases in albuminuria and podocyte loss, mitochondrial dysfunction and inflammatory cytokines, including the cGAS-STING and STAT3 signaling pathways. A 3-week treatment of 21-month-old mice with a STING inhibitor reversed the increases in inflammatory cytokines and the senescence marker p21 but also unexpectedly reversed the age-related decreases in PGC-1α, ERRα, mitochondrial complexes and Mcad expression.
2023-08-02 | PXD020051 | Pride
Project description:Male biased islet b cell dysfunction is caused by the MODY MAFA S64F variant by inducing premature aging and senescence
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