Z Gastroenterol 2007; 45 - A2_03
DOI: 10.1055/s-2007-967793

Glucosylcerebrosid accumulation in liver of bile acid beta glucosidase (Gba2) knockout mouse

Y Yildiz 1, H Matern 2, S Matern 2, T Sauerbruch 3, F Lammert 4, DW Russell 5
  • 1Medizinische Klinik I, Universität Bonn, Bonn
  • 2Medizinische Klinik III Universitätsklinikum Aachen, Aachen
  • 3Medizinische Klinik und Poliklinik I, Universitätsklinikum Bonn, Bonn
  • 4Medizinische Klinik und Poliklinik I, Universität Bonn, Bonn
  • 5Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, texas, Dallas, USA

A novel microsomal bile acid beta glucosidase (GBA2) has been purified and characterized from human liver. The bile acid beta glucosidase hydrolyzes specifically bile acid 3-O-glucosides as endogenous compounds in liver. However, GBA2 is highly expressed in many tissues, including liver, brain, testes, bone marrow, and muscle. Since some of these tissues are not involved in bile acid metabolism, a Gba2 knockout (Gba2 -/-) mouse was generated to further characterize the function(s) of GBA2.

Methods: Vector construction for Gba2 -/- generation, ES cell transformation, screening and blastocyst injections were carried out according to standard protocols. In addition, sperm analysis and in vitro fertilization were performed. We determined GBA2 protein expression by immunoblot and immunofluorescence analysis. Hepatic bile acid secretion rates as well as bile acid pool size and composition were compared between knockout mice and wild-type controls. Intracellular lipids were characterized by thin-layer chromatography and mass spectrometry.

Results and conclusions: Male Gba2 -/- mice have a fertility problem and display globozoospermia. The sperm show a defect in the acrosome, which is not able to penetrate the Zona pellucida. In contrast, Gba2 -/- mice show no profound defect in bile acid metabolism, since bile acid pool sizes and secretion rates do not differ. Of note, Gba2 -/- mice are characterized by an accumulation of glucosylcerebrosid in liver, brain, and testes, which might contribute to globozoospermia and further metabolic traits yet to be defined. We conclude that GBA2 is an ubiquitous enzyme that cleaves various lipid glucosides as endogenous compounds and plays critical roles in lipid metabolism across different tissues. We speculate that mutations of the orthologous GBA2 gene might contribute to infertility and modify the phenotypes of glucosylcerebrosid storage disorders such as Gaucher disease in humans.

Literatur: Yildiz Y. , Matern H., Thompson B., Allegood J.C., Warren R.L., Ramirez D.M.O., Hammer R.E., Hamra K., Matern S.,Russell D.W. Journal of Clinical investigations 2006 in press
Matern, H., Heinemann, H., Legler, G., Matern, S. Purification and characterization of a microsomal bile acid ß-glucosidase from human liver. J. Biol. Chem.1997, 272, 11261-11267
Matern, H., Boermans, H., Lottspeich, F., Matern, S. Molecular cloning and expression of human bile acid ß-glucosidase. J. Biol. Chem. 2001, 276, 37929-37933