Abstract:

Elevated mortality in liver transplantation-waiting list, clinical complications and scarcity of paediatric liver-donors warrant alternatives to liver transplant for treating paediatric-chronic liver diseases (CLD). Liver’s unique intrinsic capacity to regenerate damaged tissue constitutes a potential approach. However, CLD hinders liver regeneration. We hypothesized that Ketogenic Diet (KD), that ameliorates CLD, could restore liver regeneration. Nonetheless, in this seminar I present unpublished data supporting that KD-feeding impairs liver regeneration and increases mortality after partial hepatectomy in juvenile CLD-and healthy-mice. However, KD did not reduce the incidence and growth of hepatocarcinomas suggesting that KD impairs cell proliferation in a regeneration-specific manner. KD impaired one-carbon metabolism, induced a liver progenitor-like transcriptional signature before hepatectomy, deregulated the molecular machinery for liver cells exiting quiescence and proliferate as well as altered innate immune response. Consistent with methionine-deficiency in KD underlying impaired liver regeneration, methionine supplementation restored hepatic regenerative capacity and survival in juvenile healthy and diet-induced CLD-mice. This was recapitulated in CLD-livers via S-adenosylmethionine, major methionine-metabolism product, or spermidine-supplemented KD.
Altogether support that methionine-dependent metabolism sustains liver regeneration under KD-feeding in paediatric-CLD.

Biosketch:

Dr. Manuel A. Fernandez-Rojo holds a bachelor’s in biology

(1999) and a PhD in Cell Biology (2005) from the University of Barcelona (Spain). For his PhD studies on the cell biology of the protein

Caveolin-1 in the lipid droplet dynamics during liver regeneration, Manuel was awarded the Margalef prize by the University of Barcelona as recognition for the best scientific manuscript derived from a PhD Thesis (Fernandez MA et al., Science. 2006) and the highly competitive Spanish Minister of Education and Science Postdoctoral Fellowship. Afterwards, he performed postdoctoral stays in Australia for over 12 years including in Rob Parton´s Lab (University of Queensland, Brisbane), Tony Tiganis´ Lab (Monash, Melbourne) and Grant Ramm´s group (QIMR Berghofer, Brisbane).

In 2017, Manuel was awarded a TALENTO Grant (Program of Research Excellence, Madrid Government) and returned to Spain to set the Hepatic Regenerative Medicine Laboratory at the IMDEA-Food Institute (Precision Nutrition and Aging Program). He has also been awarded NHMRC and The Diabetes Australia Research Trust grant projects and he is an Honorary Associated Professor at the University of Queensland (top-40 ranked University worldwide). Manuel has provided seminal contributions to the field of hepatology, cell biology and metabolism. Moreover, he is part of the experts that provides recommendations to the Space European Agency to implement multi-omics in life Science studies in space missions. He is co-author in two Patent Cooperation Treaty and one patent applications in liver diseases and a new animal venom-derived senolytic, and recently the Ministry of Science of Spain recognized the excellence of his research with the I3-certificate. Currently, and since 2022, Manuel is part of the Inherited Cardiomyopathies laboratory at the CNIC.

Manuel´s program is to implement regenerative medicine as feasible therapy for chronic liver diseases (CLD), reduce the need of liver transplants, prevent liver cancer & metabolic/cardiovascular disorders associated to hepatic disease. He uses mouse models at different ages to recapitulate paediatric and adult liver conditions that are precursors of adult CLD. Liver transplantation represents the current “one-fits-all” standard approach in the clinical management of CLD.

Living-donor liver transplants, in which a liver portion from a compatible healthy person (usually a patient-relative) undergoes a compensatory hyperplasia to grow and substitute the receptor’s damaged liver, constitutes the major therapeutic option for some CLD cases.

Nonetheless, liver transplants are not exempt from fatal complications, liver regeneration is impaired in CLD and anti-fibrotic medicines, that may promote remodeling of tissue microenvironment to facilitate liver regeneration, are still in clinical trials and lack FDA approval.

Therefore, there is an unmet medical need for alternatives to liver transplant to treat chronic liver diseases. Thus, Manuel aims to implement feasible personalized and unbiased nutritional modifications (Precision Nutrition) promoting liver regeneration and characterize molecular basis in CLD. In addition, Manuel collaborates with, to generate a liver-drug discovery platform based on non-commercially available animal venoms to identify animal venom-derived anti-fibrotic and pro-regenerative compounds (in collaboration with Dr. Maria Ikonomopoulou, Head of the Translational Venomics Lab) and in 3D-bioprinting to build micro-livers that could be implanted in disease livers.