GLP-2 Improves Hepatic Inflammation and Fibrosis in Mdr2 Mice Via Activation of NR4a1/Nur77 in Hepatic Stellate Cells and Intestinal FXR Signaling

作者：Claudia Fuchs, Thierry Claudel, Veronika Mlitz, Alessandra Riva, Moritz Menz, Ksenia Brusilovskaya, Felix Haller, Maximilian Baumgartner, Philipp Königshofer, Lukas Unger, Wilhelm Sjöland, Hubert Scharnagl, Tatjana Stojaković, Georg Busslinger, Thomas Reiberger, Hanns–Ulrich Marschall, Michael Trauner · 发表于：Cellular and Molecular Gastroenterology and Hepatology · 年份：2023 · DOI：10.1016/j.jcmgh.2023.08.003 · 被引用次数：27 · 研究领域：Nuclear Receptors and Signaling、Macrophage Migration Inhibitory Factor、Liver physiology and pathology

Background & Aims Glucagon-like peptide (GLP)-2 may exert antifibrotic effects on hepatic stellate cells (HSCs). Thus, we aimed to test whether application of the GLP-2 analogue teduglutide has hepatoprotective and antifibrotic effects in the Mdr2/Abcb4 -/- mouse model of sclerosing cholangitis displaying hepatic inflammation and fibrosis. Methods Mdr2 -/- mice were injected daily for 4 weeks with teduglutide followed by gene expression profiling (bulk liver; isolated HSCs) and immunohistochemistry. Activated HSCs (LX2 cells) and immortalized human hepatocytes and human intestinal organoids were treated with GLP-2. mRNA profiling by reverse transcription polymerase chain reaction and electrophoretic mobility shift assay using cytosolic and nuclear protein extracts was performed. Results Hepatic inflammation, fibrosis, and reactive cholangiocyte phenotype were improved in GLP-2-treated Mdr2 -/- mice. Primary HSCs isolated from Mdr2 -/- mice and LX2 cells exposed to GLP-2 in vitro displayed significantly increased mRNA expression levels of NR4a1/Nur77 ( P < .05). Electrophoretic mobility shift assay revealed an increased nuclear NR4a1 binding after GLP-2 treatment in LX2 cells. Moreover, GLP-2 alleviated the Tgfβ-mediated reduction of NR4a1 nuclear binding activity. In vivo, GLP-2 treatment of Mdr2 -/- mice resulted in increased intrahepatic levels of muricholic acids (accordingly Cyp2c70 mRNA expression was significantly increased), and in reduced mRNA levels of Cyp7a1 and FXR...