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  3. Bile acids mediate fructose-associated liver tumour growth in mice

Bile acids mediate fructose-associated liver tumour growth in mice

  • Biochim Biophys Acta Mol Basis Dis. 2024 Mar;1870(3):167029. doi: 10.1016/j.bbadis.2024.167029.
Stefan Hargett 1,  Sujoy Lahiri 1,  Greg M Kowalski 2,  Susan Corley 3,  Marin E Nelson 1,  Carolin Lackner 4,  Ellen M Olzomer 3,  Isabella Aleksovska 3,  Brandon A Hearn 3,  Riya Shrestha 3,  Michael Janitz 3,  Mark D Gorrell 5,  Clinton R Bruce 2,  Marc Wilkins 3,  Kyle L Hoehn 6,  Frances L Byrne 7
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Medicine, University of Virginia, Charlottesville, VA 22908-0735, USA.
  • 2 School of Exercise & Nutrition Sciences, Faculty of Health, Deakin University, Geelong, Waurn Ponds, Victoria 3216, Australia.
  • 3 School of Biotechnology & Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW 2052, Australia.
  • 4 Institute of Pathology, Medical University of Graz, Graz, Austria.
  • 5 Liver Enzymes in Metabolism and Inflammation Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2006, Australia.
  • 6 Department of Pharmacology, School of Medicine, University of Virginia, Charlottesville, VA 22908-0735, USA; School of Biotechnology & Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW 2052, Australia.
  • 7 School of Biotechnology & Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: frances.byrne@unsw.edu.au.
PMID: 38325224 DOI: 10.1016/j.bbadis.2024.167029
Abstract

High fructose diets are associated with an increased risk of liver Cancer. Previous studies in mice suggest increased lipogenesis is a key mechanism linking high fructose diets to liver tumour growth. However, these studies administered fructose to mice at supraphysiological levels. The aim of this study was to determine whether liver tumour growth and lipogenesis were altered in mice fed fructose at physiological levels. To test this, we injected male C57BL/6 mice with the liver carcinogen diethylnitrosamine and then fed them diets without fructose or fructose ranging from 10 to 20 % total calories. Results showed mice fed diets with ≥15 % fructose had significantly increased liver tumour numbers (2-4-fold) and total tumour burden (∼7-fold) vs mice fed no-fructose diets. However, fructose-associated tumour burden was not associated with lipogenesis. Conversely, unbiased metabolomic analyses revealed bile acids were elevated in the sera of mice fed a 15 % fructose diet vs mice fed a no-fructose diet. Using a syngeneic ectopic liver tumour model, we show that ursodeoxycholic acid, which decreases systemic bile acids, significantly reduced liver tumour growth in mice fed the 15 % fructose diet but not mice fed a no-fructose diet. These results point to a novel role for systemic bile acids in mediating liver tumour growth associated with a high fructose diet. Overall, our study shows fructose intake at or above normal human consumption (≥15 %) is associated with increased liver tumour numbers and growth and that modulating systemic bile acids inhibits fructose-associated liver tumour growth in mice.

Keywords

Bile acids; Diethylnitrosamine; Lipogenesis; Liver tumour; Metabolomics.

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