#IDIBELLExtraordinary seminars: NASH driven liver cancer: Should we target steatosis or inflammation

The exponential increase in the consumption of refined sugar, and more specifically, high fructose corn syrup (HFCS) correlates with the increased incidence of metabolic diseases such as non-alcoholic steatohepatitis (NASH) and certain cancers such as hepatocellular carcinoma (HCC). Recent work from several laboratories, including ours suggests that fructose affects hepatosteatosis through the ‘gut-liver axis’, a physiological circuit through which gut microbiota and/or their products reach the liver via the portal circulation to provoke an inflammatory response that alters liver metabolism (1,2). Specifically, we show that that excessive fructose consumption results in gut barrier deterioration, dysbiosis, low-grade intestinal inflammation and endotoxemia, in a pre-clinical model of NASH (1). Using single nucleus RNAseq, we have recently uncovered a novel transcriptional signature in hepatocytes with both diagnostic and prognostic significance for HCC that involves pathways involved in inflammation and ER Stress (3) and that treating preclinical models with drugs that specifically target these pathways can arrest NASH and HCC progression in the absence of altering the liver or blood lipidome (4). These data will be discussed.

Hosted by Cristina Muñoz Pinedo – Preclinical and experimental research in thoracic tumors (PReTT) group

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(1) Todoric, J. et al. Fructose stimulated de novo lipogenesis is promoted by inflammation. Nat Metab 2, 1034-1045, (2020).
(2) Febbraio, M.A. & Karin, M. “Sweet death”: Fructose as a metabolic toxin that targets the gut-liver axis. Cell Metab, (2021).
(3) Carlessi R. et al. Single nucleus RNA sequencing of pre-malignant liver reveals disease associated hepatocyte state with HCC prognostic potential. Cell Genomics (in press 2023).
(4) Boslem E. Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC. In review.

Professor Mark Febbraio is a National Health and Medical Research Council of Australia Senior Principal Investigator and the Head of the Cellular and Molecular Metabolism Laboratory within the Drug Discovery Program at Monash Institute of Pharmaceutical Sciences, Monash University Australia. He is also the Founder of the recently incorporated company Celesta Therapeutics. His research is focussed on understanding mechanisms associated with exercise, obesity, type 2 diabetes and cancer and his aim is to develop novel drugs to treat lifestyle related diseases. He has authored over 280 peer reviewed papers in leading journals and has over 45,000 career citations. Throughout his career, he has won many prestigious awards including the A K McIntyre Prize for significant contributions to Australian Physiological Science (1999), the Kellion Award for the Australian Diabetes Society (2017), The Eureka Scientific Prize (2020), The GSK Award for Research Excellence (2020), The Endocrinology Society UK International Medal (2021) the Kirsten and Freddy Johansen Rigshospitalet International Award, Denmark (2022) and The Faculty of Pharmacy and Pharmaceutical Sciences, Monash University Award for Excellence in Research (2022).