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Chronic hyperinsuli...
Chronic hyperinsulinemia promotes human hepatocyte senescence
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- Baboota, Ritesh (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
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- Spinelli, R. (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
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- Erlandsson, Malin, 1972 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research
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Brandao, B. B. (författare)
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Lino, M. (författare)
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Yang, H. (författare)
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- Mardinoglu, Adil (författare)
- KTH,Science for Life Laboratory, SciLifeLab,Systembiologi
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- Bokarewa, Maria, 1963 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research
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- Boucher, Jeremie (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
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Kahn, C. R. (författare)
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- Smith, Ulf, 1943 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
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(creator_code:org_t)
- Elsevier BV, 2022
- 2022
- Engelska.
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Ingår i: Molecular Metabolism. - : Elsevier BV. - 2212-8778. ; 64
- Relaterad länk:
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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https://gup.ub.gu.se...
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Abstract
Ämnesord
Stäng
- Objective: Cellular senescence, an irreversible proliferative cell arrest, is caused by excessive intracellular or extracellular stress/damage. Increased senescent cells have been identified in multiple tissues in different metabolic and other aging-related diseases. Recently, several human and mouse studies emphasized the involvement of senescence in development and progression of NAFLD. Hyperinsulinemia, seen in obesity, metabolic syndrome, and other conditions of insulin resistance, has been linked to senescence in adipocytes and neurons. Here, we investigate the possible direct role of chronic hyperinsulinemia in the development of senescence in human hepatocytes. Methods: Using fluorescence microscopy, immunoblotting, and gene expression, we tested senescence markers in human hepatocytes subjected to chronic hyperinsulinemia in vitro and validated the data in vivo by using liver-specific insulin receptor knockout (LIRKO) mice. The consequences of hyperinsulinemia were also studied in senescent hepatocytes following doxorubicin as a model of stress-induced senescence. Furthermore, the effects of senolytic agents in insulin- and doxorubicin-treated cells were analyzed. Results: Results showed that exposing the hepatocytes to prolonged hyperinsulinemia promotes the onset of senescence by increasing the expression of p53 and p21. It also further enhanced the senescent phenotype in already senescent hepatocytes. Addition of insulin signaling pathway inhibitors prevented the increase in cell senescence, supporting the direct contribution of insulin. Furthermore, LIRKO mice, in which insulin signaling in the liver is abolished due to deletion of the insulin receptor gene, showed no differences in senescence compared to their wild-type counterparts despite having marked hyperinsulinemia indicating these are receptor-mediated effects. In contrast, the persistent hyperinsulinemia in LIRKO mice enhanced senescence in white adipose tissue. In vitro, senolytic agents dasatinib and quercetin reduced the prosenescent effects of hyperinsulinemia in hepatocytes. Conclusion: Our findings demonstrate a direct link between chronic hyperinsulinemia and hepatocyte senescence. This effect can be blocked by reducing the levels of insulin receptors or administration of senolytic drugs, such as dasatinib and quercetin.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Gastroenterologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Gastroenterology and Hepatology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Nyckelord
- Dasatinib
- Hepatocytes
- Hyperinsulinemia
- NAFLD
- Quercetin
- Senescence
- C peptide
- doxorubicin
- interleukin 18
- interleukin 32
- interleukin 8
- protein kinase B
- protein p21
- protein p53
- somatomedin C
- stromelysin
- insulin
- insulin receptor
- adipose tissue
- animal experiment
- animal model
- Article
- cell aging
- cell metabolism
- cell proliferation
- cell viability
- controlled study
- cytotoxicity
- DNA damage
- endoreduplication
- flow cytometry
- fluorescence activated cell sorting
- fluorescence intensity
- fluorescence microscopy
- gene expression
- gene overexpression
- genetic marker
- glucose blood level
- human
- human cell
- IHH cell line
- immunocytochemistry
- immunohistochemistry
- insulin signaling
- insulin treatment
- knockout mouse
- liver cell
- macrophage
- male
- mouse
- nonhuman
- phenotype
- physiological stress
- Pi3K/Akt signaling
- protein expression
- protein phosphorylation
- real time polymerase chain reaction
- receptor gene
- RNA sequencing
- Western blotting
- animal
- genetics
- insulin resistance
- metabolism
- Animals
- Humans
- Mice
- Receptor
- Insulin
- Animals
- Cellular Senescence
- Dasatinib
- metabolism
- pharmacology
- Doxorubicin
- Hepatocytes
- Humans
- Insulin
- Insulin Resistance
- Mice
- Quercetin
- Receptor
- genetics
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
Hitta via bibliotek
Till lärosätets databas
- Av författaren/redakt...
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Baboota, Ritesh
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Spinelli, R.
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Erlandsson, Mali ...
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Brandao, B. B.
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Lino, M.
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Yang, H.
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visa fler...
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Mardinoglu, Adil
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Bokarewa, Maria, ...
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Boucher, Jeremie
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Kahn, C. R.
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Smith, Ulf, 1943
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visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Gastroenterologi
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Medicinska och f ...
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och Cell och molekyl ...
- Artiklar i publikationen
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Molecular Metabo ...
- Av lärosätet
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Kungliga Tekniska Högskolan
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Göteborgs universitet