Saponara, Enrica, Penno, Carlos, Brun, Virginie, Fischer, Benoit, Brousseau, Margaret, O'Donnell, Peter, Turner, Jonathan, Graff Meyer, Alexandra, Bollepalli, Laura, Roma, Guglielmo, Orsini, Vanessa, Annunziato, Stefano, Obrecht, Michael, Beckmann, Nicolau, Saravanan, Chandrassegar, Tropberger, Philipp, Richards, Shola, Aebi, Alexandra, Ley, Svenja, Ksiazek, Iwona, Genoud, Christel, Nigsch, Florian, Tchorz, Jan, Bouwmeester, Antonius, Ruffner, Heinz, Wang, Zhongyi, Fischer, Audrey, Schadt, Heiko, Matadamas-Guzman, Meztli L, d'Ario, Giovanni, Carbone, Walter, Osmont, Arnaud and Terracciano, Luigi M (2023) Loss of Hepatic Leucine-Rich Repeat-Containing G-Protein Coupled Receptors 4 and 5 Promotes Nonalcoholic Fatty Liver Disease. The American Journal of Pathology, 193 (2). pp. 161-181. ISSN https://www.sciencedirect.com/science/article/pii/S0002944022003583?via%3Dihub

Abstract

The roof plate-specific spondin-leucine-rich repeat-containing G-protein coupled receptor 4/5 (LGR4/5)-zinc and ring finger 3 (ZNRF3)/ring finger protein 43 (RNF43) module is a master regulator of hepatic Wnt/β-catenin signaling and metabolic zonation. However, its impact on nonalcoholic fatty liver disease (NAFLD) remains unclear. The current study investigated whether hepatic epithelial cell-specific loss of the Wnt/β-catenin modulator Lgr4/5 promoted NAFLD. The 3- and 6-month-old mice with hepatic epithelial cell-specific deletion of both receptors Lgr4/5 (Lgr4/5dLKO) were compared with control mice fed with normal diet (ND) or high-fat diet (HFD). Six-month-old HFD-fed Lgr4/5dLKO mice developed hepatic steatosis and fibrosis but the control mice did not. Serum cholesterol-high-density lipoprotein and total cholesterol levels in 3- and 6-month-old HFD-fed Lgr4/5dLKO mice were decreased compared with those in control mice. An ex vivo primary hepatocyte culture assay and a comprehensive bile acid (BA) characterization in liver, plasma, bile, and feces demonstrated that ND-fed Lgr4/5dLKO mice had impaired BA secretion, predisposing them to develop cholestatic characteristics. Lipidome and RNA-sequencing analyses demonstrated severe alterations in several lipid species and pathways controlling lipid metabolism in the livers of Lgr4/5dLKO mice. In conclusion, loss of hepatic Wnt/β-catenin activity by Lgr4/5 deletion led to loss of BA secretion, cholestatic features, altered lipid homeostasis, and deregulation of lipoprotein pathways. Both BA and intrinsic lipid alterations contributed to the onset of NAFLD.

Item Type:	Article
Keywords:	Liver, Nonalcoholic Fatty Liver Disease, Lgr4, Lgr5, steatosis, fibrosis, cholestasis
Date Deposited:	28 Mar 2023 00:45
Last Modified:	28 Mar 2023 00:45
URI:	https://oak.novartis.com/id/eprint/48909