Slabber, Coenraad Frederik and Bachofner, Marc and Speicher, Tobias and Kuklin, Andrii and Fearon, Abbie Elisabeth and Padrissa-Altes, Susagna and Bogorad, Roman and Rudigier, Carla Horvath and Wust, Daria and Krautbauer, Sabrina and Hoering, Marcus and Liebisch, Gerhard and Anderson, Daniel G. and Wolfrum, Christian and Keller, Ulrich Auf Dem and Werner, Sabine (2023) The ubiquitin ligase Uhrf2 is a master regulator of cholesterol biosynthesis and is essential for liver regeneration. SCIENCE SIGNALING, 16 (787): eade8029. ISSN 1945-0877, 1937-9145
Full text not available from this repository. (Request a copy)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. Hepa-tocyte-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 bio-synthesis 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GROWTH-FACTOR; STATISTICAL-MODEL; LIPID EXTRACTION; NUCLEAR RECEPTOR; BIOTIN LIGASE; FGF RECEPTORS; PROTEIN; ISWI; DNA; MOUSE; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 26 Mar 2024 06:51 |
| Last Modified: | 26 Mar 2024 06:51 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60535 |
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