Poster Presentation 2nd Australian Cancer and Metabolism Meeting 2017

Lipogenesis is dispensable for liver tumourigenesis in mice treated with diethynitrosamine (#30)

Marin E Healy 1 , Jenny DY Chow 2 , Frances L Byrne 3 , Kyle L Hoehn 3
  1. University of Sydney, Sydney
  2. LaTrobe University, Melbourne
  3. University of New South Wales, Kensington, NSW, Australia

Primary liver cancer is one of the deadliest cancers in the world and is the cancer with the fastest growing incidence in Australia. Patients with elevated lipogenic signatures in tumor tissue have extremely poor prognosis and current evidence strongly suggests that blocking lipogenesis represents a promising approach to treat or prevent liver cancer. However, we show that mice with liver-specific knockout of ACC1 and ACC2 genes completely lack hepatic lipogenesis but develop twice the tumour burden of floxed controls exposed to the hepatocellular carcinogen diethylnitrosamine. Mechanistically, the loss of lipogenesis conserved NADPH leading to improved antioxidant defense and increased survival of damaged hepatocytes. Importantly, there were no genotype-specific differences in the hallmark risk factors for liver cancer including hepatic steatosis, adiposity, inflammation, hyperinsulinemia, or glucose intolerance. Furthermore, we showed that lipogenesis-deficient liver tumour cells were fully capable of satisfying their requirement for lipid by upregulating transporters that scavenge fats from the circulation. These data reveal an important role for ACC enzymes in antioxidant defense, cell survival and proliferation in the context of liver tumorigenesis.