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Augmented expression of gamma-glutamyl transferase 5 (GGT5) impairs testicular steroidogenesis by deregulating local oxidative stress

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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.

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Abbreviations

LCs:

Leydig cells

DM:

Type 2 diabetes

StAR:

Steroidogenic acute regulatory protein

P5:

Pregnenolone

P450scc:

P450 side-chain cleavage

ROS:

Reactive oxygen species

GSH:

Glutathione

SOD:

Superoxide dismutase

GPx:

Glutathione peroxidase

GST:

Glutathione-S-transferase

GGT:

Gamma-glutamyl transferase

HO:

Heme oxygenases

CO:

Carbon monoxide

db-cAMP:

Dibutyryl cAMP

GCs:

Germ cells

EDS:

Ethane dimethane sulphonate

DMEM:

Dulbecco’s modified Eagle’s medium

LH:

Luteinizing hormone

LHR:

Luteinizing hormone receptor

22-ROH:

22R-hydroxycholesterol

MAPK:

Mitogen-activated protein kinase

BSO:

L-buthionine-sulfoximine

SAG:

S-Acetyl glutathione

CV:

Coefficients of variation

MDA:

Malondialdehyde

ZnPP:

Zinc protoporphyrin

CG:

Chorionic gonadotropin

CdCl2 :

Cadmium chloride

ERK:

Extracellular signal-related kinase

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Acknowledgments

We are grateful to Ms. Hui Wang (Department of Medical Psychology, Fourth Military Medical University, China) for her careful assistance during the preparation of the article.

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    Authors and Affiliations

    1. Department of Histology and Embryology, Fourth Military Medical University, Xi’an, 710032, China

      Wei Li & Jie Zhao

    2. Department of Interventional Radiology, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710038, China

      Zhi-qun Wu

    3. Reproductive Medicine Center, Department of Obstetrics and Gynecology, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710038, China

      Shun Zhang

    4. Department of Nutrition and Food Hygiene, Fourth Military Medical University, Xi’an, 710032, China

      Rui Cao

    5. Research Center for Reproductive Medicine, 202 Hospital of PLA, No. 5 Guangrong Road, Heping District, Shenyang, 110000, China

      Zhi-jian Sun

    6. Department of Obstetrics and Gynecology, Xijing Hospital, Fourth Military Medical University, No. 127 Changle West Road, Xi’an, 710032, China

      Wei Zou

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    1. Wei Li
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    Correspondence to Zhi-jian Sun or Wei Zou.

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    Wei Li and Zhi-qun Wu contributed equally to this work.

    The authors thank the National Natural Science Foundation of China for financially supporting this research under NSFC Project: 31271248, 31440064, and 81101959.

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    Li, W., Wu, Zq., Zhang, S. et al. Augmented expression of gamma-glutamyl transferase 5 (GGT5) impairs testicular steroidogenesis by deregulating local oxidative stress. Cell Tissue Res 366, 467–481 (2016). https://doi.org/10.1007/s00441-016-2458-y

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