Identification and characterization of novel splice variants of human farnesoid X receptor

Mustonen, Enni-Kaisa; Lee, Serene M. L.; Niess, Hanno; Schwab, Matthias; Pantsar, Tatu und Burk, Oliver (2021): Identification and characterization of novel splice variants of human farnesoid X receptor. In: Archives of Biochemistry and Biophysics, Bd. 705, 108893

Abstract

Farnesoid X receptor (FXR, NR1H4) is a ligand-activated nuclear receptor, which regulates bile acid, lipid and glucose metabolism. Due to these functions, FXR has been investigated as a potential drug target for the treatment of liver diseases, such as primary biliary cholangitis and non-alcoholic steatohepatitis. Based on the previously described four splice variants, it has been suggested that alternative promoter usage and splicing may have an impact on total FXR activity as a result of encoding functionally diverse variants. Here we aimed for a systematic analysis of human hepatic FXR splice variants. In addition to the previously described FXR alpha 1-4, we identified four novel splice variants (FXR alpha 5-8) in human hepatocytes, which resulted from previously undetected exon skipping events. These newly identified isoforms displayed diminished DNA binding and impaired transactivation activities. Isoform FXR alpha 5, which suppressed the transactivation activity of the functional isoform FXR alpha 2, was further characterized as deficient in heterodimerization, coactivator recruitment and ligand binding. These findings were further supported by molecular dynamics simulations, which offered an explanation for the behavior of this isoform on the molecular level. FXR alpha 5 exhibited low uniform expression levels in nearly all human tissues. Our systematic analysis of FXR splice variants in human hepatocytes resulted in the identification of four novel FXR isoforms, which all proved to be functionally deficient, but one novel variant, FXR alpha 5, also displayed dominant negative activity. The possible associations with and roles of these novel isoforms in human liver diseases require further investigation.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0003-9861
• Sprache: Englisch