Tysnd1 deficiency in mice interferes with the peroxisomal localization of PTS2 enzymes, causing lipid metabolic abnormalities and male infertility.

Peroxisomes are subcellular organelles involved in lipid metabolic processes, including those of very-long-chain fatty acids and branched-chain fatty acids, among others. Peroxisome matrix proteins are synthesized in the cytoplasm. Targeting signals (PTS or peroxisomal targeting signal) at the C-terminus (PTS1) or N-terminus (PTS2) of peroxisomal matrix proteins mediate their import into the organelle. In the case of PTS2-containing proteins, the PTS2 signal is cleaved from the protein when transported into peroxisomes. The functional mechanism of PTS2 processing, however, is poorly understood. Previously we identified Tysnd1 (Trypsin domain containing 1) and biochemically characterized it as a peroxisomal cysteine endopeptidase that directly processes PTS2-containing prethiolase Acaa1 and PTS1-containing Acox1, Hsd17b4, and ScpX. The latter three enzymes are crucial components of the very-long-chain fatty acids ß-oxidation pathway. To clarify the in vivo functions and physiological role of Tysnd1, we analyzed the phenotype of Tysnd1(-/-) mice. Male Tysnd1(-/-) mice are infertile, and the epididymal sperms lack the acrosomal cap. These phenotypic features are most likely the result of changes in the molecular species composition of choline and ethanolamine plasmalogens. Tysnd1(-/-) mice also developed liver dysfunctions when the phytanic acid precursor phytol was orally administered. Phyh and Agps are known PTS2-containing proteins, but were identified as novel Tysnd1 substrates. Loss of Tysnd1 interferes with the peroxisomal localization of Acaa1, Phyh, and Agps, which might cause the mild Zellweger syndrome spectrum-resembling phenotypes. Our data established that peroxisomal processing protease Tysnd1 is necessary to mediate the physiological functions of PTS2-containing substrates.

Gene expression profile of the neonatal female mouse brain after administration of testosterone propionate.

INTRODUCTION: Clinical care decisions for peripubertal adolescents with gender dysphoria (GD) should be made carefully. Furthermore, the identification of biomarkers is very important for rapid and accurate diagnosis of GD in young people. AIM: The aim of this study was to investigate gene expression profiles during masculinization of the neonatal female mouse brain by testosterone and to identify biomarkers related to GD. METHODS: Microarray analysis was performed using RNAs extracted from the brains of neonatal mice treated by intraperitoneal injection of testosterone propionate during the sexual determination period. Sequence motif enrichment analysis for sex hormone receptor responsive elements was performed for the flanking regions of genes that showed significant expression changes following administration of testosterone propionate. MAIN OUTCOME MEASURES: We revealed a gene set with marked changes in expression during brain masculinization of neonatal female mice following administration of testosterone propionate. RESULTS: We identified 334 genes that showed differential expression in the masculinized neonatal female brain after testosterone propionate treatment. Interestingly, most of these genes are not reported to be expressed in a sexually dimorphic manner. Moreover, sequence motif enrichment analysis suggested that masculinization of the neonatal female brain by testosterone was controlled more by estrogen receptors than androgen receptors. CONCLUSIONS: Differences in genes that are expressed differentially following administration of testosterone injection from known sexually dimorphic genes suggest that many GD-related genes are upregulated during female brain masculinization. The gene set identified in this study provides a basis to better understand the mechanisms of GD and delineate its associated biomarkers.

4-Hydroxydocosahexaenoic acid, a potent peroxisome proliferator-activated receptor gamma agonist alleviates the symptoms of DSS-induced colitis.

(5E,7Z,10Z,13Z,16Z,19Z)-4-Hydroxy-5,7,10,13,16,19-docosahexaenoic acid (4-OHDHA) is a potential agonist of peroxisome proliferator-activated receptor-gamma (PPARgamma) and antidiabetic agent as has been previously reported. As PPARgamma agonists may also have anti-inflammatory functions, in this study, we investigated whether 4-OHDHA has an inhibitory effect on expression of inflammatory genes in vitro and whether 4-OHDHA could relieve the symptoms of dextran sodium sulfate (DSS)-induced colitis in a murine model of inflammatory bowel disease. 4-OHDHA inhibited production of nitric oxide and expression of a subset of inflammatory genes including inducible nitric oxide synthase (Nos2/iNOS) and interleukin 6 (Il6) by lipopolysaccharide (LPS)-activated macrophages. In addition, 4-OHDHA-treated mice when compared to control mice not receiving treatment recovered better from the weight loss caused by DSS-induced colitis. Changes in disease activity index (DAI) of 4-OHDHA-treated mice were also more favorable than for control mice and were comparable with mice treated with a typical anti-inflammatory-drug, 5-aminosalichylic acid (5-ASA). These results suggest that 4-OHDHA has potentially clinically useful anti-inflammatory effects mediated by suppression of inflammatory gene expression.