A research team led by YANG Wulin from the Hefei Institutes of Physical Science (HFIPS) of the Chinese Academy of Sciences reported that a metabolic regulation mechanism may play a role in malignant transformation of non-alcoholic steatohepatitis to liver tumor. This work was published in International Journal of Biological Sciences.

Fatty liver refers to a common disease in liver marked with an excessive accumulation of fat in its cells. One of fatty liver diseases, non-alcoholic fatty liver disease (NAFLD) is the team explored. The development of non-alcoholic fatty liver disease is staged, in which nonalcoholic steatohepatitis (NASH), is a critical stage and may turn into liver cancer.  

The team was curious about the turning. They began with a mouse model that mimics the development of human fatty liver disease by studying changes in gene expression information that occur at various stages in the progression of NAFLD.

In each stage of the disease, they conducted deeper analysis on gene differential expressions and gene set variations. They found that carcinogenic signals were extensively activated during NASH stage. 

Meanwhile, fatty acid metabolism was specifically up-regulated by the LPL/FABP4/CPT1 signaling axis. Together, the two may promote the formation of tumor-initiating cells, and then malignant transformation begins.  

On this basis, they conducted further laboratory studies, which showed that inhibition of LPL/FABP4/CPT1 signaling axis effectively inhibited liver tumor growth in vivo.  

In addition, in vitro cell experiments also confirmed that targeted inhibition of the metabolic axis significantly reduced the self-renewal and proliferation capacity of liver cancer stem cells.

The researchers believe that inhibition of fatty acid metabolic signaling axis may prevent NAFLD from transforming into liver cancer, providing new ideas for the prevention of NASH-associated liver cancer.   

Model diagram: In the NASH stage, a variety of oncogenic signals and fatty acid metabolism signal axis are activated in concert, which is conducive to the formation of tumor stem cells and the occurrence of malignant transformation. (Image by LIU Yu)