Identification of a key regulator of bile acid production and liver regeneration
A "Science Signaling" paper by the Werner group (IMHS) describes an essential function of the ubiquitin ligase Uhrf2 in liver regeneration. Loss of Uhrf2 in hepatocytes increased the production of cholesterol, resulting in the accumulation of toxic bile acids that caused liver failure after partial hepatectomy.
The liver has a remarkable regenerative capacity, which allows rapid and complete regeneration after acute injury. However, if the insult is too severe and/or chronic, the regenerative capacity is insufficient, resulting in liver failure or development of fibrosis, cirrhosis or even liver cancer.
Therefore, it is important to develop innovative strategies to improve the regeneration process, which requires the identification of genes, proteins and pathways that are dysregulated when regeneration is impaired. Slabber et al. used mice lacking the receptors for fibroblast growth factors 1 and 2 (FGFR1 and FGFR2) in hepatocytes as a model for impaired regeneration. Using quantitative proteomics analysis of nuclear and cytoplasmic lysates of liver from FGF receptor-deficient and control mice, they identified the ubiquitin ligase Uhrf2 as a target of FGFR signalling in the regenerating liver. Mice lacking Uhrf2 in hepatocytes showed severe necrosis and reduced hepatocyte proliferation after partial hepatectomy, leading to liver failure.
In hepatocytes, Uhrf2 interacted with several chromatin remodelling proteins and suppressed the expression of cholesterol biosynthesis genes. This caused accumulation of cholesterol and toxic bile acids after liver injury. Treatment with a bile acid scavenger rescued the necrotic phenotype, hepatocyte proliferation, and regenerative capacity of the liver in Uhrf2-deficient mice. These results identify Uhrf2 as an essential regulator of liver regeneration and highlight the importance of epigenetic metabolic regulation in this process. They also open new avenues for the potential future treatment of impaired liver regeneration by activation of the FGFR-Uhrf2 signaling axis.
Link to the publication in external page "Science Signaling".