Chronic hyperinsulinemia promotes human hepatocyte senescence

• 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

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