HCG-induced endoplasmic reticulum stress triggers apoptosis and reduces steroidogenic enzyme expression through activating transcription factor 6 in leydig cells of the testis

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Title
HCG-induced endoplasmic reticulum stress triggers apoptosis and reduces steroidogenic enzyme expression through activating transcription factor 6 in leydig cells of the testis
Author(s)
S J Park; T S Kim; C K Park; S H Lee; J M Kim; Kyu-Sun Lee; I K Lee; J W Park; M A Lawson; D S Lee
Bibliographic Citation
Journal of Molecular Endocrinology, vol. 50, no. 2, pp. 151-166
Publication Year
2013
Abstract
Endoplasmic reticulum (ER) stress generally occurs in secretory cell types. It has been reported that Leydig cells, which produce testosterone in response to human chorionic gonadotropin (hCG), express key steroidogenic enzymes for the regulation of testosterone synthesis. In this study, we analyzed whether hCG induces ER stress via three unfolded protein response (UPR) pathways in mouse Leydig tumor (mLTC-1) cells and the testis. Treatment with hCG induced ER stress in mLTC-1 cells via the ATF6, IRE1a/XBP1, and eIF2a/GADD34/ATF4 UPR pathways, and transient expression of 50 kDa protein activating transcription factor 6 (p50ATF6) reduced the expression level of steroidogenic 3b-hydroxy-steroid dehydrogenase O5-O4-isomerase (3b-HSD) enzyme. In an in vivo model, high-level hCG treatment induced expression of p50ATF6 while that of steroidogenic enzymes, especially 3b-HSD, 17a-hydroxylase/C17-20 lyase (CYP17), and 17b-hydrozysteroid dehydrogenase (17b-HSD), was reduced. Expression levels of steroidogenic enzymes were restored by the ER stress inhibitor tauroursodeoxycholic acid (TUDCA). Furthermore, lentivirus-mediated transient expression of p50ATF6 reduced the expression level of 3b-HSD in the testis. Protein expression levels of phospho-JNK, CHOP, and cleaved caspases-12 and -3 as markers of ER stress-mediated apoptosis markedly increased in response to high-level hCG treatment in mLTC-1 cells and the testis. Based on transmission electron microscopy and H&E staining of the testis, it was shown that abnormal ER morphology and destruction of testicular histology induced by high-level hCG treatment were reversed by the addition of TUDCA. These findings suggest that hCG-induced ER stress plays important roles in steroidogenic enzyme expression via modulation of the ATF6 pathway as well as ER stress-mediated apoptosis in Leydig cells.
Keyword
Activating transaction factor 6ER stressLeydig cellsSteroidogenic enzyme expressionTestosterone
ISSN
0952-5041
Publisher
Bioscientifica Ltd
DOI
http://dx.doi.org/10.1530/JME-12-0195
Type
Article
Appears in Collections:
1. Journal Articles > Journal Articles
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