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

Park, Sun-Ji; Kim, Tae-Shin; Park, Choon‐Keun; Lee, Sang‐Hee; Kim, Jin Man; Lee, Kyu-Sun; Lee, Inkyu; Park, Jeen‐Woo; Lawson, Mark A.; Lee, Dong‐Seok

doi:10.1530/jme-12-0195

Cited by 66 publications

(57 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The UPR is crucial for the function of secretory cells, including β cells, hepatocytes, and osteoblasts (Gass et al, 2004; Wu and Kaufman, 2006; Volchuk and Ron, 2010), all of which have heavy protein synthesis demands and thus rely on the proper function of the ER in order to maintain secretory output. It has also been recently described in the Leydig cell where UPR induction causes a decrease in steroid output through activation of the ATF6 pathway and ER stress-mediated apoptosis (Park et al, 2013). …”

Section: Control Of Mrna Translationmentioning

confidence: 99%

Translational control of gene expression in the gonadotrope

Kim

Minh‐Ha

Lawson

2014

Molecular and Cellular Endocrinology

View full text Add to dashboard Cite

The study of gene expression in gonadotropes has largely focused on the variety of mechanisms regulating transcription of the gonadotropin genes and ancillary factors that contribute to the overall phenotype and function of these cells in reproduction. However, there are aspects of the response to GNRH signaling that are not readily explained by changes at the level of transcription. As our understanding of regulation at the level of mRNA translation has increased, it has become evident that GNRH receptor signaling engages multiple aspects of translational regulation. This includes activation of cap-dependent translation initiation, translational pausing caused by the unfolded protein response and RNA binding protein interaction. Gonadotropin mRNAs and the mRNAs of other factors that control the transcriptional and signaling responses to GNRH have been identified as targets of regulation at the level of translation. In this review we examine the impact of translational control of the expression of gonadotropin genes and other genes relevant to GNRH-mediated control of gonadotrope function.

show abstract

Section: Control Of Mrna Translationmentioning

confidence: 99%

Translational control of gene expression in the gonadotrope

Kim

Minh‐Ha

Lawson

2014

Molecular and Cellular Endocrinology

View full text Add to dashboard Cite

show abstract

“…However, hCG has higher in vitro activity than LH in terms of cAMP production (28). Moreover, Park and coworkers have recently demonstrated that hCG induces steroidogenic enzyme in vivo in male mice and in vitro in mouse Leydig tumor cells (mLTC-1) (29). In particular, in vitro, after multiple injection of hCG, mRNA levels of steroidogenic enzymes (STAR, 3βHSD, CYP17, and 17βHSD) decreased markedly in mLTC-1 cells (29).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, Park and coworkers have recently demonstrated that hCG induces steroidogenic enzyme in vivo in male mice and in vitro in mouse Leydig tumor cells (mLTC-1) (29). In particular, in vitro, after multiple injection of hCG, mRNA levels of steroidogenic enzymes (STAR, 3βHSD, CYP17, and 17βHSD) decreased markedly in mLTC-1 cells (29). Similarly, in vivo models show an increased production of mRNA and proteins of 3βHSD, P450c17, and 17βHSD3 during the first 12 h after daily hCG treatment (29).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, in vitro, after multiple injection of hCG, mRNA levels of steroidogenic enzymes (STAR, 3βHSD, CYP17, and 17βHSD) decreased markedly in mLTC-1 cells (29). Similarly, in vivo models show an increased production of mRNA and proteins of 3βHSD, P450c17, and 17βHSD3 during the first 12 h after daily hCG treatment (29). This increase is followed by a gradual decrease in further 24 h (29).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Human chorionic gonadotropin stimulation gives evidence of differences in testicular steroidogenesis in Klinefelter syndrome, as assessed by liquid chromatography–tandem mass spectrometry

Belli

Santi

Leoni

et al. 2016

European Journal of Endocrinology

View full text Add to dashboard Cite

Background: Men with Klinefelter syndrome (KS) show hypergonadotropic hypogonadism, but the pathogenesis of hypotestosteronemia remains unclear. Testicular steroidogenesis in KS men was evaluated over three decades ago after human chorionic gonadotropin (hCG) stimulation, but inconclusive results were obtained. Intriguingly, some recent studies show increased intratesticular testosterone concentrations in men with KS. Objective: To analyze serum steroid profile, as a proxy of testicular steroidogenesis, after hCG stimulation in KS compared with control men. Design: A prospective, longitudinal, case-control, clinical trial. Methods: Thirteen KS patients (36 ± 9 years) not receiving testosterone (TS) replacement therapy and 12 eugonadic controls (32 ± 8 years) were enrolled. Serum steroids were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) at baseline and for five consecutive days after intramuscular injection of 5000 IU hCG. Results: Progesterone (P), 17-hydroxyprogesterone (17OHP), TS, and estradiol (E2) showed a significant increase (P < 0.001) after hCG stimulation in both groups. On the contrary, androstenedione (AS) and dehydroepiandrosterone did not increase after hCG stimulation. The 17OHP/P ratio increased in both groups (P < 0.001), the TS/AS ratio (17β-hydroxysteroid dehydrogenase type 3 (17βHSD3) activity) did not increase after hCG in any group, and the E2/TS ratio (aromatase activity) increased significantly in both groups (P = 0.009 in KS and P < 0.001 in controls). Luteinizing hormone decreased after hCG in both groups (P = 0.014 in KS and P < 0.001 in controls), whereas follicle-stimulating hormone decreased only in control men (P < 0.001). Conclusion: This study demonstrates for the first time using LC-MS/MS that Leydig cells of KS men are able to respond to hCG stimulation and that the first steps of steroidogenesis are fully functional. However, the TS production in KS men is impaired, possibly related to reduced hydroxysteroid deydrogenase activity due to an unfavorable intratesticular metabolic state.

show abstract

“…LH induces T production in testicular Leydig cells. Exogenous hCG acts similar to LH through the same LH receptor (LHR) (Saez, 1994; Park et al ., 2013). In Leydig cells, LH or HCG binds to LHR to activate adenylyl cyclase and convert ATP into cAMP.…”

Section: Introductionmentioning

confidence: 99%

The SET protein promotes androgen production in testicular Leydig cells

Zhang

Zhu

et al. 2018

Andrology

View full text Add to dashboard Cite

SummaryApproximately 40% of middle‐aged men exhibit symptoms of late‐onset hypogonadism (LOH). However, the mechanism of androgen deficiency is still currently unclear. As shown in our previous studies, the SET protein is expressed in testicular Leydig cells and ovarian granule cells. This study was designed to investigate the effect of the SET protein on androgen production in Leydig cells. The AdCMV/SET and AdH1siRNA/SET adenoviruses were individually transduced into a cultured mouse Leydig cell line (mLTC‐1) with or without human chorionic gonadotropin (HCG) stimulation in vitro. The primary mouse Leydig cells were used to confirm the main data from mLTC‐1 cells. The SET protein was expressed in the cytoplasm and nucleus of mLTC‐1 cells. Testosterone production was significantly increased in mLTC‐1 cells overexpressing the SET protein compared with the control group (p < 0.05), whereas testosterone production was significantly decreased in the SET knockdown mLTC‐1 cells (p < 0.05). Consistent with the testosterone levels, the expression levels of the steroidogenic acute regulatory (StAR) and cytochrome P450c17α‐hydroxylase (CYP17a1) mRNAs and proteins synchronously changed according to the expression level of the SET protein. Interestingly, the expression of the SET protein was significantly increased in the mLTC‐1 cells stimulated with 0.04 and 0.1 U/mL hCG. In the mLTC‐1 cells transfected with AdH1siRNA/SET and concurrently stimulated with 0.1 U/mL hCG, both testosterone production and StAR expression were significantly lower than in the cells without SET knockdown (p < 0.05). In conclusion, the SET protein participates in regulating testosterone production by increasing the expression of StAR and CYP17a1, and it may be a downstream factor of the classic luteinizing hormone (LH)/luteinizing hormone receptor (LHR) signaling pathway. This study improves our understanding of the intracellular mechanism of testicular steroidogenesis and the pathophysiological mechanism of LOH in the aging male.

show abstract

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

Cited by 66 publications

References 44 publications

Translational control of gene expression in the gonadotrope

Translational control of gene expression in the gonadotrope

Human chorionic gonadotropin stimulation gives evidence of differences in testicular steroidogenesis in Klinefelter syndrome, as assessed by liquid chromatography–tandem mass spectrometry

The SET protein promotes androgen production in testicular Leydig cells

Contact Info

Product

Resources

About