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Targeting Senescent Hepatocytes for Treatment of Metabolic Dysfunction-associated Steatotic Liver Disease and Multi-organ Dysfunction

ABSTRACT: Targeting Senescent Hepatocytes for Treatment of Metabolic Dysfunction-associated Steatotic Liver Disease and Multi-organ Dysfunction

PROVIDER: PRJNA1218242 | ENA |

REPOSITORIES: ENA

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Targeting Senescent Hepatocytes for Treatment of Metabolic Dysfunction-associated Steatotic Liver Disease and Multi-organ Dysfunction

Project description:Senescent hepatocytes accumulate in metabolic dysfunction-associated steatotic liver disease (MASLD) and are linked to worse clinical outcomes. However, their heterogeneity and lack of specific markers have made them difficult to target therapeutically. Here, we define a senescent hepatocyte gene signature (SHGS) using in vitro and in vivo models and show that it tracks with MASLD progression/regression across mouse models and large human cohorts. Single-nucleus RNA-sequencing and functional studies reveal that SHGS+ hepatocytes originate from p21+ cells, lose key liver functions and release factors that drive disease progression. One such factor, GDF15, increases in circulation alongside SHGS+ burden and disease progression. Through chemical screening, we identify senolytics that selectively eliminate SHGS+ hepatocytes and improve MASLD in mice. Notably, SHGS enrichment also correlates with dysfunction in other organs. These findings establish SHGS+ hepatocytes as key drivers of MASLD and highlight a potential therapeutic strategy for targeting senescent cells in liver disease and beyond.

2025-02-21 | GSE288534 | GEO

Binding of the spike of SARS-CoV-2 to steatotic hepatocytes promotes metabolic dysfunction

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

Aging Promotes Metabolic Dysfunction-associated Steatotic Liver Disease and Multi-Organ Dysfunction by Inducing Ferroptotic Stress

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.

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Aging Promotes Metabolic Dysfunction-associated Steatotic Liver Disease and Multi-Organ Dysfunction by Inducing Ferroptotic Stress

Project description:Aging Promotes Metabolic Dysfunction-associated Steatotic Liver Disease and Multi-Organ Dysfunction by Inducing Ferroptotic Stress

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Inter-organ transmission of hepatocellular senescence induces multi-organ dysfunction through the TGFβ signalling pathway.

Project description:Cellular senescence is associated with aging but also impacts various physiological and pathological processes such as embryonic development and wound healing. Factors secreted by senescent cells can affect their microenvironment, including local spreading of senescence. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure. Why the latter occurs is poorly understood however, the presence of hepatic senescence is associated with poor prognosis and extrahepatic organ failure in acute liver disease. Here, using genetic mouse models of hepatocyte-specific senescence, we demonstrate senescence development in extrahepatic organs and associated organ dysfunction in response to liver senescence. In patients with acute indeterminate hepatitis, the extent of hepatocellular senescence predicts the occurrence of extrahepatic dysfunction, need for liver transplantation and mortality. We identify the Transforming Growth Factor β (TGFβ) pathway as a critical mediator of systemic spread of senescence and TGFβ inhibition blocks senescence transmission to other organs preventing renal dysfunction. Our results highlight the systemic consequences of organ-specific senescence which, independent of aging, contributes to multi-organ dysfunction.

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Inter-organ transmission of hepatocellular senescence induces multi-organ dysfunction through the TGFbeta signalling pathway

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2024-08-23 | GSE267196 | GEO

Deep proteome profiling of metabolic dysfunction-associated steatotic liver disease

Project description:Analyze human biopsies for the investigation of metabolic dysfunction-associated steatotic liver disease (MASLD). We also analyzed plasma samples for biomarker discovery. And analyzed the role of the impact of the adipose tissue on plasma proteins in relation to MASLD

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Oxidised apolipoprotein peptidome characterise metabolic dysfunction-associated steatotic liver disease.Oxidised apolipoprotein peptidome characterise metabolic dysfunction-associated steatotic liver disease.

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IL-17 Signaling in Steatotic Hepatocytes and Macrophages Promotes Alcoholic Liver Disease-induced Hepatocellular Carcinoma [II]

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IL-17 Signaling in Steatotic Hepatocytes and Macrophages Promotes Alcoholic Liver Disease-induced Hepatocellular Carcinoma [I]

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