Chronic hyperinsulinemia promotes human hepatocyte senescence

Area of Science:

• Cellular biology
• Metabolic diseases
• Aging research

Background:

• Cellular senescence is an irreversible cell cycle arrest linked to aging and metabolic diseases like non-alcoholic fatty liver disease (NAFLD).
• Hyperinsulinemia, common in obesity and insulin resistance, has been implicated in senescence in various cell types, including adipocytes and neurons.
• The specific role of hyperinsulinemia in liver cell senescence, particularly in the context of NAFLD, requires further investigation.

Purpose of the Study:

• To investigate the direct role of chronic hyperinsulinemia in the development of senescence in human hepatocytes.
• To explore the impact of hyperinsulinemia on both induced and established cellular senescence in liver cells.
• To evaluate the potential of senolytic agents in mitigating hyperinsulinemia-induced senescence.

Main Methods:

• Human hepatocytes were exposed to chronic hyperinsulinemia in vitro, and senescence markers (p53, p21) were assessed using fluorescence microscopy, immunoblotting, and gene expression analysis.
• In vivo validation involved liver-specific insulin receptor knockout (LIRKO) mice to examine the effects of abolished hepatic insulin signaling on senescence.
• The efficacy of senolytic agents (dasatinib, quercetin) was tested in hepatocytes treated with insulin or doxorubicin to induce senescence.

Main Results:

• Prolonged hyperinsulinemia in vitro significantly increased senescence markers (p53, p21) in human hepatocytes, exacerbating existing senescence.
• Insulin signaling pathway inhibitors blocked the pro-senescence effects of insulin, confirming its direct role.
• LIRKO mice showed no increase in liver senescence despite hyperinsulinemia, indicating receptor-mediated effects, while senescence was enhanced in their white adipose tissue.
• Senolytic agents dasatinib and quercetin effectively reduced hyperinsulinemia-induced senescence in hepatocytes.

Conclusions:

• Chronic hyperinsulinemia directly induces senescence in human hepatocytes via insulin receptor-mediated pathways.
• Targeting hepatic insulin receptors or utilizing senolytic drugs offers potential therapeutic strategies to counteract hyperinsulinemia-driven liver cell senescence.
• These findings establish a direct link between hyperinsulinemia and hepatocyte senescence, relevant to metabolic and aging-related liver diseases.