Background:
Liver cancer is the 3rd leading cause of cancer-related deaths worldwide. While virus-related liver cancers are declining, obesity-related liver cancers are rising including in Australia. Obesity is largely caused by excess consumption of high sugar/high fat diets and a sedentary lifestyle. Identifying obesity-related factors that increase the risk of liver cancer or tumour growth is important if we want to prevent and develop better treatments.
Rationale and Aim:
In this study we investigated fructose because high fructose diets are associated with obesity and an increased risk of liver cancer. Previous studies indicate that increased lipogenesis (fat synthesis) is a key mechanism linking dietary fructose to liver tumour growth. However, these studies have administered fructose to mice at non-physiological levels in diets that do not reflect a typical human diet. Therefore, the aim of this study was to determine whether fructose altered liver tumour growth and lipogenesis when given at physiological levels (10-20% of total calories) in a human-relevant diet.
Methods:
Male C57BL/6 mice were injected with the liver carcinogen diethylnitrosamine and then fed one of six isocaloric diets containing 45% fat, 35% carbohydrate, and 20% protein (% total calories). Carbohydrate source was the only variable, coming from corn starch, glucose, sucrose, or 3 different ratios of glucose (G) and fructose (F); G:F 1:1, G:F 2:1, and G:F 1:2.
Results:
Diets with ≥15% total calories as fructose (G:F 1:1, G:F 1:2, and sucrose) had the greatest liver tumour burden. However, fructose-associated tumour burden was not associated with lipogenesis. Metabolomics revealed serum bile acids were elevated in mice fed the fructose-containing G:F 1:1 vs. the glucose diet. Mechanistically, we showed that UDCA (which decreases the bile acid deoxycholic acid) significantly reduced liver tumour growth in mice fed the fructose diet but not the glucose diet.
Conclusions:
The clinical implications of this study are 1) fructose intake at or above normal human consumption (≥15 %) may promote liver tumour growth, 2) we have uncovered a novel role for bile acids in mediating fructose-induced liver tumour growth, and 3) UDCA (an FDA-approved drug) is a promising new treatment for obesity-related liver cancer.