The ubiquitin ligase Uhrf2 is a master regulator of cholesterol biosynthesis and is essential for liver regeneration

Coenraad Frederik Slabber, Marc Bachofner, Tobias Speicher, Andrii Kuklin, Abbie Elisabeth Fearon, Susagna Padrissa-Altés, Roman Bogorad, Carla Horváth Rudigier, Daria Wüst, Sabrina Krautbauer, Marcus Höring, Gerhard Liebisch, Daniel G. Anderson, Christian Wolfrum, Ulrich auf dem Keller, Sabine Werner*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Fibroblast growth factors (FGFs) are key regulators of the remarkable regenerative capacity of the liver. Mice lacking FGF receptors 1 and 2 (Fgfr1 and Fgfr2) in hepatocytes are hypersensitive to cytotoxic injury during liver regeneration. Using these mice as a model for impaired liver regeneration, we identified a critical role for the ubiquitin ligase Uhrf2 in protecting hepatocytes from bile acid accumulation during liver regeneration. During regeneration after partial hepatectomy, Uhrf2 expression increased in an FGFR-dependent manner, and Uhrf2 was more abundant in the nuclei of liver cells in control mice compared with FGFR-deficient mice. Hepatocyte-specific Uhrf2 knockout or nanoparticle-mediated Uhrf2 knockdown caused extensive liver necrosis and impaired hepatocyte proliferation after partial hepatectomy, resulting in liver failure. In cultured hepatocytes, Uhrf2 interacted with several chromatin remodeling proteins and suppressed the expression of cholesterol biosynthesis genes. In vivo, the loss of Uhrf2 resulted in cholesterol and bile acid accumulation in the liver during regeneration. Treatment with a bile acid scavenger rescued the necrotic phenotype, hepatocyte proliferation, and the regenerative capacity of the liver in Uhrf2-deficient mice subjected to partial hepatectomy. Our results identify Uhrf2 as a key target of FGF signaling in hepatocytes and its essential function in liver regeneration and highlight the importance of epigenetic metabolic regulation in this process. Liver regeneration in mice depends on the suppression of cholesterol biosynthesis by the ubiquitin ligase Uhrf2. Signaling mediated by growth factors of the FGF family and their receptors Fgfr1 and Fgfr2 contributes to liver repair and regeneration by promoting the detoxification of hepatocyte-damaging compounds. Slabber et al. identified a role for the ubiquitin ligase Uhrf2 in FGFR-dependent hepatoprotection. Partial hepatectomy increased the expression of Uhrf2 in the liver in a manner that required Fgfr1 and Fgfr2. In hepatocytes, Uhrf2 interacted with chromatin remodeling proteins and inhibited the expression of genes involved in cholesterol biosynthesis. Hepatectomized mice lacking Uhrf2 in hepatocytes developed liver failure characterized by increased necrosis and the accumulation of cholesterol and bile acids, which was rescued by a bile acid scavenger. Thus, FGF-induced Uhrf2 protects the regenerating liver from damaging bile acids by reducing the expression of cholesterol biosynthesis genes, likely in cooperation with epigenetic regulators. —Annalisa M. VanHook
Original languageEnglish
Article numbereade8029
JournalScience Signaling
Volume16
Issue number787
Number of pages21
ISSN1945-0877
DOIs
Publication statusPublished - 2023

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