Deleting the mouse Hsd17b1 gene results in a hypomorphic Naglu allele and a phenotype mimicking a lysosomal storage disease.
| Title: | Deleting the mouse Hsd17b1 gene results in a hypomorphic Naglu allele and a phenotype mimicking a lysosomal storage disease. |
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| Authors: | Jokela H; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine and Turku Center for Disease Modeling, University of Turku, FI-20014, Turku, Finland.; Hakkarainen J; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine and Turku Center for Disease Modeling, University of Turku, FI-20014, Turku, Finland.; Kätkänaho L; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine and Turku Center for Disease Modeling, University of Turku, FI-20014, Turku, Finland.; Pakarinen P; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine and Turku Center for Disease Modeling, University of Turku, FI-20014, Turku, Finland.; Ruohonen ST; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine and Turku Center for Disease Modeling, University of Turku, FI-20014, Turku, Finland.; Tena-Sempere M; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine and Turku Center for Disease Modeling, University of Turku, FI-20014, Turku, Finland.; Department of Cell Biology, Physiology and Immunology, and Instituto Maimónides de Investigación Biomédica de Córdoba & Hospital Universitario Reina Sofia (IMIBIC/HURS), ES-14004, Cordoba, Spain.; Zhang FP; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine and Turku Center for Disease Modeling, University of Turku, FI-20014, Turku, Finland.; Poutanen M; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine and Turku Center for Disease Modeling, University of Turku, FI-20014, Turku, Finland. matti.poutanen@utu.fi.; Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, SE-41345, Gothenburg, Sweden. matti.poutanen@utu.fi. |
| Source: | Scientific reports [Sci Rep] 2017 Nov 27; Vol. 7 (1), pp. 16406. Date of Electronic Publication: 2017 Nov 27. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: London : Nature Publishing Group, copyright 2011- |
| MeSH Terms: | Alleles* ; Gene Deletion* ; Genetic Association Studies* ; Phenotype*; 17-Hydroxysteroid Dehydrogenases/*genetics ; Lysosomal Storage Diseases/*genetics; Glycosaminoglycans/metabolism ; Lysosomal Storage Diseases/diagnosis ; Lysosomal Storage Diseases/metabolism ; Lysosomes/metabolism ; Mucopolysaccharidosis III/diagnosis ; Mucopolysaccharidosis III/genetics ; Mucopolysaccharidosis III/metabolism ; Animals ; Disease Models, Animal ; Gene Expression ; Genetic Loci ; Male ; Mice |
| Abstract: | 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. |
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| Substance Nomenclature: | 0 (Glycosaminoglycans); EC 1.1.- (17-Hydroxysteroid Dehydrogenases); EC 1.1.- (hydroxysteroid (17-beta) dehydrogenase 1, mouse) |
| Entry Date(s): | Date Created: 20171129 Date Completed: 20190712 Latest Revision: 20190712 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC5703720 |
| DOI: | 10.1038/s41598-017-16618-5 |
| PMID: | 29180785 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't