RT Journal Article SR Electronic T1 β-catenin-activated hepatocellular carcinomas are addicted to fatty acids JF Gut JO Gut FD BMJ Publishing Group Ltd and British Society of Gastroenterology SP gutjnl-2017-315448 DO 10.1136/gutjnl-2017-315448 A1 Nadia Senni A1 Mathilde Savall A1 David Cabrerizo Granados A1 Marie-Clotilde Alves-Guerra A1 Chiara Sartor A1 Isabelle Lagoutte A1 Angélique Gougelet A1 Benoit Terris A1 Hélène Gilgenkrantz A1 Christine Perret A1 Sabine Colnot A1 Pascale Bossard YR 2018 UL http://gut.bmj.com/content/early/2018/04/11/gutjnl-2017-315448.abstract AB Objectives CTNNB1-mutated hepatocellular carcinomas (HCCs) constitute a major part of human HCC and are largely inaccessible to target therapy. Yet, little is known about the metabolic reprogramming induced by β-catenin oncogenic activation in the liver. We aimed to decipher such reprogramming and assess whether it may represent a new avenue for targeted therapy of CTNNB1-mutated HCC.Design We used mice with hepatocyte-specific oncogenic activation of β-catenin to evaluate metabolic reprogramming using metabolic fluxes on tumourous explants and primary hepatocytes. We assess the role of Pparα in knock-out mice and analysed the consequences of fatty acid oxidation (FAO) using etomoxir. We explored the expression of the FAO pathway in an annotated human HCC dataset.Results β-catenin-activated HCC were not glycolytic but intensively oxidised fatty acids. We found that Pparα is a β-catenin target involved in FAO metabolic reprograming. Deletion of Pparα was sufficient to block the initiation and progression of β-catenin-dependent HCC development. FAO was also enriched in human CTNNB1-mutated HCC, under the control of the transcription factor PPARα.Conclusions FAO induced by β-catenin oncogenic activation in the liver is the driving force of the β-catenin-induced HCC. Inhibiting FAO by genetic and pharmacological approaches blocks HCC development, showing that inhibition of FAO is a suitable therapeutic approach for CTNNB1-mutated HCC.