Molecular Mechanisms Linking Nonalcoholic Steatohepatitis to Cancer

Abstract

Watch a video presentation of this article Watch an interview with the author Answer questions and earn CME.

FIG 1

Metabolic syndrome–initiated mechanisms key to NASH‐HCC. Excessive lipid accumulation (a key inciting event) causes oxidative stress, resulting in mitochondrial dysfunction. This leads to changes in lipid metabolism, changes in growth and development pathways, and changes in the immune system that promote HCC.

FIG 2

The importance of IGF signaling in NASH‐HCC. Insulin resistance and resultant hyperinsulinemia drive activation of growth pathways, including IGF‐1/AKT and mTOR. ⁴¹ IGF‐1 exerts anti‐inflammatory, antilipogenic, and antiapoptotic effects in animal models of NASH, but, paradoxically, IGF‐1R is often upregulated in HCC tissue, suggesting that the antiapoptotic effect may be driving carcinogenesis and promoting dysregulated growth. ²⁰

FIG 3

Kupffer cells are activated via TREM‐1, whose activation leads to secretion of inflammatory cytokines, including TNF‐α and IL‐6. These induce alterations in NF‐κB signaling, thereby promoting dedifferentiation and proliferation of hepatocytes.