Metabolic disorder is one of the causes of liver cancer. Mitochondria is responsible for oxidation using NAD, which is produced in Step 4 of the citrate–malate shuttle system. In high obesity or insulin resistance (diabetes) patients, their body contains large amounts of fatty acid, the shuttle system might not generate sufficient NAD to metabolize the fat efficiently. They also exhibit a low NAD level. Thus, it is more likely for obesity or diabetes patients to develop liver cancer.
Moreover, overloading of mitochondria may occur. There is an increase in reactive oxygen species level in the liver. Those species are highly reactive and would attack liver cells. They can damage the DNA strands. Cells with DNA damage may divide abnormally. They might grow into cancer cells, resulting in HCC.
Another risk factor is mutations and overexpressed citrate–malate shuttle. A high frequency mutated gene in a wide range of cancers, Ras oncogene, has a significantly close association to HCC. Many HCC patients carry this gene. They also have abnormal citrate–malate shuttle. The research of Dalian Medical University shows that there is a noticeable increase in the HCC patients’ citrate and malate levels, suggesting the possibility of higher activity of citrate–malate shuttle. This mechanism is effective when TCA cycle activity is low. The shuttle also helps the production of fatty acid and lactic acid.
In liver cancer cells, the TCA cycle is blocked, causing accumulation of excess pyruvate. It is a signal of the body defense mechanism. Normally, the cancer cells would die under a high pyruvate level. However, the overexpressed citrate–malate shuttle can remove the excessive pyruvate. In this situation, the natural cell death of liver tumor will not occur. The cancer cells can keep growing.
In addition, high shuttle activity is linked to increase in fatty acid generation. It is also a risk factor of HCC.