title: Augmented expression of gamma-glutamyl transferase 5 (GGT5) impairs testicular steroidogenesis by deregulating local oxidative stress.
abstract: An increasingly pro-oxidant environment has been widely implicated in causing dysfunction of testicular steroidogenesis, but little progress has been made in understanding the underlying molecular mechanism. Here, we report that gamma-glutamyl transferase 5 (GGT5), a key metabolism component responsible for the catalysis of important anti-oxidant glutathione (GSH), is predominantly expressed in mammalian Leydig cells (LCs). Deregulated GGT5 expression negatively correlates with testosterone deficiency in the testes of type 2 diabetic mice. Consistently, overexpression of GGT5 potentiates the susceptibility of TM3 LCs to spontaneous oxidative stress during luteinizing hormone (LH)-stimulated steroidogenesis. From a mechanistic standpoint, the deleterious effect of GGT5 overexpression on testicular steroidogenesis may stem from an alteration of the local redox state because of GSH deficiency. The above-mentioned response might involve the impairment of extracellular signal-related kinase activation mediated directly by oxidative injury or indirectly by abnormal P38 activation, which in turn inhibits steroidogenic acute regulatory protein abundance in mitochondria and thus significantly sabotages the rate-limiting step during LH-induced steroidogenesis. Alternatively, GGT5 overexpression induces heme oxygenase 1 (HO-1) expression, which, as a key catalyst responsible for the oxidative degradation of heme, may inhibit the activities of the cytochrome P450 monooxygenases, thus substantially impairing testicular steroidogenesis. These results, coupled with the differential roles of mitogen-activated protein kinases and HO-1 signaling in spermatogenesis, lead us to propose a model in which a delicate balance between these two pathways modulated by the GGT5/oxidative stress cascade plays a central role during LH-stimulated steroidogenesis.
authors.affiliation: Department of Histology and Embryology, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Interventional Radiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China.
authors.forename: Zhi-Qun
authors.initials: ZQ
authors.lastname: Wu
authors.affiliation: Reproductive Medicine Center, Department of Obstetrics and Gynecology, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China.
authors.forename: Shun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Nutrition and Food Hygiene, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Cao
authors.affiliation: Department of Histology and Embryology, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Research Center for Reproductive Medicine, 202 Hospital of PLA, No. 5 Guangrong Road, Heping District, Shenyang, 110000, China. sunzhijian@126.com.
authors.forename: Zhi-Jian
authors.initials: ZJ
authors.lastname: Sun
authors.affiliation: Department of Obstetrics and Gynecology, Xijing Hospital, Fourth Military Medical University, No. 127 Changle West Road, Xi'an, 710032, China. zouwei@fmmu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Zou
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D004150:Dipeptidases / Q000378:metabolism*; D005978:Glutathione / Q000172:deficiency / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007985:Leydig Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007986:Luteinizing Hormone / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D013256:Steroids / Q000096:biosynthesis*; D013737:Testis / Q000201:enzymology* / Q000473:pathology*; D013739:Testosterone / Q000172:deficiency; D015854:Up-Regulation / Q000187:drug effects; D005723:gamma-Glutamyltransferase / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D013256:Steroids; D013739:Testosterone; D007986:Luteinizing Hormone; D051547:Heme Oxygenase-1; D005723:gamma-Glutamyltransferase; D048051:p38 Mitogen-Activated Protein Kinases; D004150:Dipeptidases; C405510:gamma-glutamyl leukotrienase; D005978:Glutathione
keywords: Gamma-glutamyl transferase (GGT5); Heme oxygenase 1 (HO-1); Leydig cells (LCs); Oxidative stress; Steroidogenesis