ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development

Area of Science:

• Hepatology
• Oncology
• Immunology

Background:

• Endoplasmic reticulum (ER) stress is linked to liver diseases like nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC).
• The precise role of ER stress in obesity-driven liver cancer remains unclear.

Purpose of the Study:

• To investigate the contribution of ER stress to obesity-induced liver tumorigenesis.
• To elucidate the mechanisms by which ER stress promotes NASH and HCC.

Main Methods:

• Feeding wild-type (WT) and MUP-uPA mice (with induced hepatocyte ER stress) a high-fat diet.
• Assessing insulin resistance, liver damage, immune cell infiltration, lipogenesis, NASH signs, and HCC development.
• Analyzing the role of tumor necrosis factor (TNF) and inflammatory macrophages.

Main Results:

• MUP-uPA mice showed increased liver damage, immune infiltration, and lipogenesis compared to WT mice.
• MUP-uPA mice developed classical NASH and steatohepatitic HCC.
• NASH and HCC development were dependent on TNF produced by inflammatory macrophages.

Conclusions:

• Hepatocyte ER stress significantly contributes to obesity-driven NASH and HCC development.
• Inflammatory macrophages and TNF are critical mediators in ER stress-induced liver tumorigenesis.
• Targeting ER stress and macrophage-mediated inflammation may offer therapeutic strategies for liver cancer.