RT Journal Article
T1 Deleting the mouse Hsd17b1 gene results in a hypomorphic Naglu allele and a phenotype mimicking a lysosomal storage disease.
A1 Jokela, Heli
A1 Hakkarainen, Janne
A1 Kätkänaho, Laura
A1 Pakarinen, Pirjo
A1 Ruohonen, Suvi T
A1 Tena-Sempere, Manuel
A1 Zhang, Fu-Ping
A1 Poutanen, Matti
K1 17-hydroxysteroid dehydrogenases
K1 Alleles
K1 Disease models, animal
K1 Gene deletion
AB HSD17B1 is a steroid metabolising enzyme. We have previously generated knockout mice that had the entire coding region of Hsd17b1 replaced with lacZ-neo cassette (Hsd17b1-LacZ/Neo mice). This resulted in a 90% reduction of HSD17B1 activity, associated with severe subfertility in the knockout females. The present study indicates that Hsd17b1-LacZ/Neo male mice have a metabolic phenotype, including reduced adipose mass, increased lean mass and lipid accumulation in the liver. During the characterisation of this metabolic phenotype, it became evident that the expression of the Naglu gene, located closely upstream of Hsd17b1, was severely reduced in all tissues analysed. Similar results were obtained from Hsd17b1-LacZ mice after removing the neo cassette from the locus or by crossing the Hsd17b1-LacZ/Neo mice with transgenic mice constitutively expressing human HSD17B1. The deficiency of Naglu caused the accumulation of glycosaminoglycans in all studied mouse models lacking the Hsd17b1 gene. The metabolic phenotypes of the Hsd17b1 knockout mouse models were recapitulated in Naglu knockout mice. Based on the data we propose that the Hsd17b1 gene includes a regulatory element controlling Naglu expression and the metabolic phenotype in mice lacking the Hsd17b1 genomic region is caused by the reduced expression of Naglu rather than the lack of Hsd17b1.
PB Nature Publishing Group
YR 2017
FD 2017-11-13
LK http://hdl.handle.net/10668/11849
UL http://hdl.handle.net/10668/11849
LA en
NO Jokela H, Hakkarainen J, Kätkänaho L, Pakarinen P, Ruohonen ST, Tena-Sempere M, et al. Deleting the mouse Hsd17b1 gene results in a hypomorphic Naglu allele and a phenotype mimicking a lysosomal storage disease. Sci Rep. 2017 Nov 27;7(1):16406
NO Tis work was supported in part by the Academy of Finland and the Sigrid Juselius Foundation. We thank K. Asp, K. Hovirinta, H. Liljenbäck, M.-R. Kajaala, N. Messner, M. Niiranen, H. Niittymäki, E. Nyman and J. Palmu at Turku Center for Disease Modeling (www.tcdm.f) for their skillful technical assistance in various stages of this study. A special thank you for A. Hakkarainen, H. Heikelä and J. Mäki-Jouppila for technical assistance. Tank you J. Tiala and N. Saarinen-Aaltonen, Forendo Pharma, for help with the HSD17B activity assays. We would also like to acknowledge Bioinformatics Unit at the Turku Centre for Biotechnology and Biocenter Finland for the data analysis of RNA sequencing.
DS RISalud
RD Apr 8, 2025