Hydroxysteroid (17ß) dehydrogenase 12 is essential for metabolic homeostasis in adult mice.

Hydroxysteroid 17ß dehydrogenase 12 (HSD17B12) is suggested to be involved in the elongation of very long chain fatty acids. Previously, we have shown a pivotal role for the enzyme during mouse development. In the present study we generated a conditional Hsd17b12 knockout (HSD17B12cKO) mouse model by breeding mice homozygous for a floxed Hsd17b12 allele with mice expressing the tamoxifen-inducible Cre recombinase at the ROSA26 locus. Gene inactivation was induced by administering tamoxifen to adult mice. The gene inactivation led to a 20% loss of body weight within 6 days, associated with drastic reduction in both white (83% males, 75% females) and brown (65% males, 60% females) fat, likely due to markedly reduced food and water intake. Furthermore, the knockout mice showed sickness behavior and signs of liver toxicity, specifically microvesicular hepatic steatosis and increased serum alanine aminotransferase (4.6-fold in males, 7.7-fold in females). The hepatic changes were more pronounced in females than males. Proinflammatory cytokines, such as interleukin-6 (IL-6), IL-17, and granulocyte colony-stimulating factor, were increased in the HSD17B12cKO mice indicating an inflammatory response. Serum lipidomics study showed an increase in the amount of dihydroceramides, despite the dramatic overall loss of lipids. In line with the proposed role for HSD17B12 in fatty acid elongation, we observed accumulation of ceramides, dihydroceramides, hexosylceramides, and lactosylceramides with shorter than 18-carbon fatty acid side chains in the serum. The results indicate that HSD17B12 is essential for proper lipid homeostasis and HSD17B12 deficiency rapidly results in fatal systemic inflammation and lipolysis in adult mice.

Hydroxysteroid (17ß) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice.

Hydroxysteroid (17ß) dehydrogenases (HSD17Bs) form an enzyme family characterized by their ability to catalyze reactions in steroid and lipid metabolism. In the present study, we characterized the phenotype of HSD17B13-knockout (HSD17B13KO) mice deficient in Hsd17b13. In these studies, hepatic steatosis was detected in HSD17B13KO male mice, indicated by histologic analysis and by the increased triglyceride concentration in the liver, whereas reproductive performance and serum steroid concentrations were normal in HSD17B13KO mice. In line with these changes, the expression of key proteins in fatty acid synthesis, such as FAS, acetyl-CoA carboxylase 1, and SCD1, was increased in the HSD17B13KO liver. Furthermore, the knockout liver showed an increase in 2 acylcarnitines, suggesting impaired mitochondrial ß-oxidation in the presence of unaltered malonyl CoA and AMPK expression. The glucose tolerance did not differ between wild-type and HSD17B13KO mice in the presence of lower levels of glucose 6-phosphatase in HSD17B13KO liver compared with wild-type liver. Furthermore, microgranulomas and increased portal inflammation together with up-regulation of immune response genes were observed in HSD17B13KO mice. Our data indicate that disruption of Hsd17b13 impairs hepatic-lipid metabolism in mice, resulting in liver steatosis and inflammation, but the enzyme does not play a major role in the regulation of reproductive functions.-Adam, M., Heikelä, H., Sobolewski, C., Portius, D., Mäki-Jouppila, J., Mehmood, A., Adhikari, P., Esposito, I., Elo, L. L., Zhang, F.-P., Ruohonen, S. T., Strauss, L., Foti, M., Poutanen, M. Hydroxysteroid (17ß) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice.

The Hydroxysteroid (17ß) Dehydrogenase Family Gene HSD17B12 Is Involved in the Prostaglandin Synthesis Pathway, the Ovarian Function, and Regulation of Fertility.

The hydroxysteroid (17beta) dehydrogenase (HSD17B)12 gene belongs to the hydroxysteroid (17ß) dehydrogenase superfamily, and it has been implicated in the conversion of estrone to estradiol as well as in the synthesis of arachidonic acid (AA). AA is a precursor of prostaglandins, which are involved in the regulation of female reproduction, prompting us to study the role of HSD17B12 enzyme in the ovarian function. We found a broad expression of HSD17B12 enzyme in both human and mouse ovaries. The enzyme was localized in the theca interna, corpus luteum, granulosa cells, oocytes, and surface epithelium. Interestingly, haploinsufficiency of the HSD17B12 gene in female mice resulted in subfertility, indicating an important role for HSD17B12 enzyme in the ovarian function. In line with significantly increased length of the diestrous phase, the HSD17B+/- females gave birth less frequently than wild-type females, and the litter size of HSD17B12+/- females was significantly reduced. Interestingly, we observed meiotic spindle formation in immature follicles, suggesting defective meiotic arrest in HSD17B12+/- ovaries. The finding was further supported by transcriptome analysis showing differential expression of several genes related to the meiosis. In addition, polyovular follicles and oocytes trapped inside the corpus luteum were observed, indicating a failure in the oogenesis and ovulation, respectively. Intraovarian concentrations of steroid hormones were normal in HSD17B12+/- females, whereas the levels of AA and its metabolites (6-keto prostaglandin F1alpha, prostaglandin D2, prostaglandin E2, prostaglandin F2α, and thromboxane B2) were decreased. In conclusion, our study demonstrates that HSD17B12 enzyme plays an important role in female fertility through its role in AA metabolism.

5-(2-Mercaptoethyl)-1H-tetrazole: Facile Synthesis and Application for the Preparation of Water Soluble Nanocrystals and Their Gels.

A facile method for the preparation of the novel capping ligand 5-(2-mercaptoethyl)-1H-tetrazole for the stabilization of water-soluble nanocrystals was developed. This effective synthetic procedure is based on the cycloaddition of sodium azide to 3,3'-dithiobis(propionitrile) followed by the reductive cleavage of a S-S bond with triphenylphosphine. The structure of the synthesized compound was confirmed by single-crystal X-ray analysis. A target tetrazole was successfully applied for the direct aqueous synthesis of CdTe and Au nanocrystals. CdTe nanocrystals capped with 5-(2-mercaptoethyl)-1H-tetrazole were found to reveal high photoluminescence efficiencies (up to 77 %). Nanocrystals capped with this tetrazole ligand are able to build 3D structures in a metal-ion-assisted gelation process in aqueous solution. Critical point drying of the as-formed hydrogels allowed the preparation of the corresponding aerogels, while preserving the mesoporous structure.

Liver lipid metabolism is altered by increased circulating estrogen to androgen ratio in male mouse.

Estrogens are suggested to lower the risk of developing metabolic syndrome in both sexes. In this study, we investigated how the increased circulating estrogen-to-androgen ratio (E/A) alters liver lipid metabolism in males. The cytochrome P450 aromatase (P450arom) is an enzyme converting androgens to estrogens. Male mice overexpressing human aromatase enzyme (AROM+ mice), and thus have high circulating E/A, were used as a model in this study. Proteomics and gene expression analyses indicated an increase in the peroxisomal ß-oxidation in the liver of AROM+ mice as compared with their wild type littermates. Correspondingly, metabolomic analysis revealed a decrease in the amount of phosphatidylcholines with long-chain fatty acids in the plasma. With interest we noted that the expression of Cyp4a12a enzyme, which specifically metabolizes arachidonic acid (AA) to 20-hydroxy AA, was dramatically decreased in the AROM+ liver. As a consequence, increased amounts of phospholipids having AA as a fatty acid tail were detected in the plasma of the AROM+ mice. Overall, these observations demonstrate that high circulating E/A in males is linked to indicators of higher peroxisomal ß-oxidation and lower AA metabolism in the liver. Furthermore, the plasma phospholipid profile reflects the changes in the liver lipid metabolism.

Gold Nanoparticle-Decorated Diatom Biosilica: A Favorable Catalyst for the Oxidation of d-Glucose.

Diatoms are unicellular algae of enormous biodiversity that occur in all water habitats on earth. Their cell walls are composed of amorphous biosilica and exhibit species-specific nanoporous to microporous and macroporous patterning. Therefore, diatom biosilica is a promising renewable material for various applications, such as in catalysis, drug-delivery systems, and biophotonics. In this study, diatom biosilica of three different species (Stephanopyxis turris, Eucampia zodiacus, and Thalassiosira pseudonana) was used as support material for gold nanoparticles using a covalent coupling method. The resulting catalysts were applied for the oxidation of d-glucose to d-gluconic acid. Because of its high specific surface area, well-established transport pores, and the presence of small, homogeneously distributed gold nanoparticles on the surface, diatom biosilica provides a highly catalytically active surface and advanced accessibility to the active sites. In comparison to those of the used reference supports, higher catalytic activities (up to 3.28 × 10-4 mmolGlc s-1 mgAu -1 for T. pseudonana biosilica) and slower deactivation were observed for two of the diatom biosilica materials. In addition, diatom biosilica showed very high gold-loading capacities (up to 45 wt %), with a homogeneous nanoparticle distribution.

3D assembly of silica encapsulated semiconductor nanocrystals.

Non-ordered porous networks, so-called aerogels, can be achieved by the 3D assembly of quantum dots (QDs). These materials are well suited for photonic applications, however a certain quenching of the photoluminescence (PL) intensity is observed in these structures. This PL quenching is mainly attributed to the energy transfer mechanisms that result from the close contact of the nanoparticles in the network. Here, we demonstrate the formation of a novel aerogel material with non-quenching PL behaviour by non-classical, reversible gel formation from tetrazole capped silica encapsulated QDs. Monitoring of the gelation/degelation by optical spectroscopy showed that the optical properties of the nanocrystals could be preserved in the 3D network since no spectral shifts and lifetime shortening, which can be attributed to the coupling between QDs, are observed in the gels as compared to the original colloidal solutions. In comparison with other QD-silica monoliths, QDs in our gels are homogeneously distributed with a distinct and controllable distance. In addition we show that the silica shell is porous and allows metal ions to pass through the shell and interact with the QD core causing detectable changes of the emission properties. We further show the applicability of this gelation method to other QD materials which sets the stage for facile preparation of a variety of mixed gel structures.

Peritubular myoid cells have a role in postnatal testicular growth.

FSH stimulates testicular growth by increasing Sertoli cell proliferation and elongation of seminiferous cords. Little is known about the peritubular myoid cells in testicular development. In order to investigate the role of peritubular myoid cells in early testicular growth in rodents, two traditional models to induce testicular growth were used: FSH treatment and hemicastration. In order to affect proliferation of peritubular myoid cells, both treatments were combined with imatinib, a tyrosine kinase inhibitor. In addition, effects of imatinib on human testicular peritubular cell proliferation were investigated. Testicular weight, diameter and length of seminiferous cords, numbers of germ, Sertoli and BrdU-positive cells and FSH-levels were measured. FSH treatment and hemicastration increased length of the seminiferous cords and testicular weight by increasing first the early proliferation of peritubular myoid cells and later also the proliferation of the Sertoli cells. Imatinib blocked the FSH and hemicastration -induced testicular hypertrophy and decreased the proliferation of PDGF-stimulated human testicular peritubular cells in vitro. Present results provide new evidence that peritubular myoid cells have an important role in postnatal testicular growth.