Hydroxysteroid 17-beta dehydrogenase 1 (HSD17B1) is an enzyme catalyzing the reduction of estrone (E1) to estradiol (E2), as well as androstenedione (Adione) to testosterone (T). To elucidate the physiological function of HSD17B1, we generated knockout mice with disrupted Hsd17b1 gene using targeted ES cells (clone 10231) obtained from KOMP repository (www.komp.org). In these ES cells the whole coding region of Hsd17b1 was replaced with LacZ/Neo cassette, expressing the reporter gene. As previously shown by us, the homozygous Hsd17b1-LacZ/Neo females were found to be subfertile and have a defect in pseudopregnancy maintenance, likely caused by the imbalance in ovarian steroid synthesis. In addition, the Hsd17b1-LacZ/Neo males present with a metabolic phenotype, including reduced adipose mass, increased lean mass and lipid accumulation in the liver. During the characterization of the metabolic phenotype, it became evident that the expression of N-acetyl-alpha-glucosaminidase (Naglu) gene, located 8399-739 bp upstream of the Hsd17b1 transcription start site, was severely reduced (13-40-fold) in all tissues analyzed in Hsd17b1-LacZ/Neo mice. Furthermore, similar results were obtained from Hsd17b1-LacZ mice after removing the Neo cassette or by crossing the Hsd17b1-LacZ/Neo mice with transgenic mice constitutively expressing human HSD17B1. Deficiency of the Naglu gene causes the accumulation of glycosaminglycans (GAGs) in several tissues, and accordingly, GAG accumulation was observed in all the above mentioned mouse models lacking the genomic region coding for Hsd17b1. Furthermore, biochemically and morphologically similar metabolic phenotype, mimicking lysosomal storage disease, was observed both in Naglu knockout mice (with the presence of active HSD17B1), and all the mouse models lacking 2.3 kb long genomic region of Hsd17b1 gene. Thus, the data indicate the presence of a strong Naglu enhancer inside the Hsd17b1 gene, and the metabolic phenotype in mice lacking the Hsd17b1 genomic region is caused by the off target effect.
20 - 23 May 2017
European Society of Endocrinology