RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state

• Published in: Nature communications Vol. 13; no. 1; p. 334
• Main Authors: Belenguer, Germán, Mastrogiovanni, Gianmarco, Pacini, Clare, Hall, Zoe, Dowbaj, Anna M, Arnes-Benito, Robert, Sljukic, Aleksandra, Prior, Nicole, Kakava, Sofia, Bradshaw, Charles R, Davies, Susan, Vacca, Michele, Saeb-Parsy, Kourosh, Koo, Bon-Kyoung, Huch, Meritxell
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 17.01.2022; Nature Publishing Group UK; Nature Portfolio
• Subjects: Adult; Animals; Cancer; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Differentiation; Cell Proliferation; Diet; Dietary supplements; Differentiation; Fatty liver; Fatty Liver - pathology; Gene Deletion; Gene Expression Regulation; Hepatocytes; Hepatocytes - metabolism; Hepatocytes - pathology; Hepatomegaly - pathology; Humans; Hyperplasia; Lipid Droplets - metabolism; Lipid metabolism; Lipid Metabolism - genetics; Lipidomics; Lipids; Liver; Liver - metabolism; Liver - pathology; Liver cancer; Liver diseases; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver Regeneration; Malignancy; Metabolism; Mice; Organoids; Prognosis; Regeneration; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Wnt protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27923-z

RNF43/ZNRF3 negatively regulate WNT signalling. Both genes are mutated in several types of cancers, however, their contribution to liver disease is unknown. Here we describe that hepatocyte-specific loss of Rnf43/Znrf3 results in steatohepatitis and in increase in unsaturated lipids, in the absence of dietary fat supplementation. Upon injury, Rnf43/Znrf3 deletion results in defective hepatocyte regeneration and liver cancer, caused by an imbalance between differentiation/proliferation. Using hepatocyte-, hepatoblast- and ductal cell-derived organoids we demonstrate that the differentiation defects and lipid alterations are, in part, cell-autonomous. Interestingly, ZNRF3 mutant liver cancer patients present poorer prognosis, altered hepatic lipid metabolism and steatohepatitis/NASH signatures. Our results imply that RNF43/ZNRF3 predispose to liver cancer by controlling the proliferative/differentiation and lipid metabolic state of hepatocytes. Both mechanisms combined facilitate the progression towards malignancy. Our findings might aid on the management of those RNF43/ZNRF3 mutated individuals at risk of developing fatty liver and/or liver cancer.