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How Fatty Liver Disease May Transform Into Liver Cancer

A new study finds that the regulation of a particular metabolic mechanism might prevent the malignant transformation of non-alcoholic streatohepatitis into liver cancer.

Liver cancer is one of the leading causes of cancer-related deaths worldwide. With increasing food intake and sedentary lifestyles, these habits have intensified the global epidemic of metabolic syndrome. Based on previous studies, it was observed that patients with metabolic syndrome have a higher incidence of liver cancer than those without metabolic syndrome. Researchers are now looking into non-alcoholic fatty liver disease and studying its relation to metabolic syndrome.

Hepatocellular carcinoma is the most neglected complication of non-alcoholic fatty liver disease and probably the most clinically challenging to tackle. Non-alcoholic fatty liver disease is staged and can develop from simple steatosis to non-alcoholic steatohepatitis, then to liver fibrosis and even cirrhosis, and finally to hepatocellular carcinoma, or liver cancer.

Intrigued by this turning, a team led by Yang Wulin from the Hefei Institutes of Physical Science (HFIPS) of the Chinese Academy of Sciences looked into this development and report that a metabolic regulation mechanism may play a part in the malignant transformation of non-alcoholic streatohepatitis to liver tumour.

The team started by analysing the gene expression profile of Stelic Animal Model (STAM) mice at different stages of non-alcoholic fatty liver disease progression. In each stage of the disease, they conducted deeper analysis on gene differential expressions and gene set variations, and found that carcinogenic signals were extensively activated during the non-alcoholic streatohepatitis stage.

The analysis of gene expression profiles also revealed that the LPL/FABP4/CPT1 signalling axis, which is responsible for lipid metabolism, was upregulated. Taken together, the results suggest that the carcinogenic signals and LPL/FABP4/CPT1 signalling axis could encourage the formation of tumour-initiating cells and drive malignant transformation.

Based on these observations, Yang and team conducted further laboratory studies, which showed that inhibiting the LPL/FABP4/CPT1 signalling molecules effectively delayed tumour growth in mice models, and in vitro cell experiments with targeted inhibition of those signalling molecules also reduced self-renewal and proliferation capacity of liver cancer stem cells. This suggests that the activation of LPL/FABP4/CPT1 axis in the non-alcoholic streatohepatitis stage may be important to the viability of tumour-initiating stem cells in liver tissue.

From their study, the team now believes that the inhibition of fatty acid metabolic signalling axis could prevent non-alcoholic fatty liver disease/non-alcoholic streatohepatitis from developing into liver cancer, presenting a new strategy for the prevention of non-alcoholic streatohepatitis-associated liver cancer. [APBN]

Source: Yang et al. (2021). Targeted Inhibition of LPL/FABP4/CPT1 fatty acid metabolic axis can effectively prevent the progression of nonalcoholic steatohepatitis to liver cancer. International journal of biological sciences, 17(15), 4207.