Glucose-Regulated Protein, 78-Kilodalton Is a Modulator of Luteinizing Hormone Receptor Expression in Luteinizing Granulosa Cells in Rats1

Kogure, Kayoko; Nakamura, Kazuto; Ikeda, Sadatomo; Kitahara, Yoshikazu; Nishimura, Toshio; Iwamune, Masayuki; Minegishi, Takashi

doi:10.1095/biolreprod.112.101873

Cited by 21 publications

(17 citation statements)

References 35 publications

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“…In the present study, mRNA expressions of aat and afp at g55 and grp78 and gen at g90 were decreased in the HFD group compared to the CON group. Early studies also found that these homeostasis-related genes’ mRNA expression is relatively concordant in ovary with proteins [35,36]. Our previous study has confirmed that aat and afp might promote primordial follicles formation, and grp78 and gen could protect primordial follicles from transforming to primary follicles [37].…”

Section: Discussionmentioning

confidence: 54%

Effect of High Fat Dietary Intake during Maternal Gestation on Offspring Ovarian Health in a Pig Model

Che

Yang

et al. 2016

Nutrients

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Excessive fat intake is a global health concern as women of childbearing age increasingly ingest a high fat diet. We therefore determined the association of a maternal high fat diet in pregnancy with offspring ovarian health during the gestation and postnatal female offspring in pig a model. Thirty-two Yorkshire gilts with similar bodyweights mated at the third estrus were randomly assigned to two nutrition levels of either a control (CON, crude fat: 7.27%) or a high fat diet (HFD, crude fat: 11.78%). Ovary samples were collected during the fetal (Day 55 (g55) and Day 90 of gestation (g90)) and offspring (prepuberty Day 160 (d160) and age at puberty) period to detect ovary development, antioxidant status and apoptosis cells. Maternal HFD did not influence notch signaling gene expression, which regulates primordial follicle formation and transformation, and ovarian histological effect at g55 and g90. However, maternal HFD reduced the numbers of large follicles at d160 and small follicle numbers upon puberty compared to CON in offspring. The results also revealed that the antioxidant index of total antioxidative capability (T-AOC), cytoplasmic copper/zinc superoxide dismutase (CuZn-SOD), glutathione peroxidase (GPx) activities and mRNA expression were higher in the CON than the HFD at g90 and d160, whereas, malondialdehyde (MDA) concentration was decreased in the CON. Maternal HFD increased the inhibitor of the apoptosis-related gene of B-cell lymphoma-2 (bcl2) mRNA expression at g90 and d160, whereas, pro-apoptotic-related gene bcl-2 assaciated X protein (bax) was reduced. These data show that the maternal high fat diet does not delay fetal ovarian development, but it changes ovarian health by the induction of oxidative stress and accelerating cell apoptosis in offspring.

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Section: Discussionmentioning

confidence: 54%

Effect of High Fat Dietary Intake during Maternal Gestation on Offspring Ovarian Health in a Pig Model

Che

Yang

et al. 2016

Nutrients

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“…Previous studies have suggested that ER stress is involved in a series of reproductive physiological processes in mammals. For example, decreased ER stress is beneficial to increased placental growth (6), and ER stress mediated by GRP78 is essential for corpus luteum formation and for maintaining normal secretory functions (20). As a crucial player in the ER stress signaling pathway, ATF6 is present in the extravillous trophoblasts, myoblasts, and cartilage (24,30), and the expression of ATF6 in various cells and tissues implies that it may play different roles in different physiological processes.…”

Section: Discussionmentioning

confidence: 99%

ATF6 knockdown decreases apoptosis, arrests the S phase of the cell cycle, and increases steroid hormone production in mouse granulosa cells

Xiong

Chen

Lin

et al. 2017

American Journal of Physiology-Cell Physiology

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Activating transcription factor 6 (ATF6), a sensor protein located in the endoplasmic reticulum (ER) membrane, is an important factor in the ER stress signaling pathway. ER stress is known to be involved in folliculogenesis, follicular growth, and ovulation; however, the physiological function of ATF6 in mouse granulosa cells remains largely unknown. The aim of this study was to assess the role of ATF6 in mouse granulosa cells with respect to apoptosis, the cell cycle, and steroid hormone production, as well as several key genes related to follicular development, via RNA interference, immunohistochemical staining, real-time quantitative PCR, Western blotting, flow cytometry, terminal deoxynucleotidyltransferase-mediated deoxy-UTP nick end labeling (TUNEL) assay, and ELISA. Immunohistochemical staining revealed that ATF6 was extensively distributed in the granulosa cells of various ovarian follicles and oocytes in adult female mice. FSH or LH treatment significantly increased ATF6 protein levels in mouse granulosa cells. In the meantime, a recombinant plasmid was used to deplete ATF6 successfully using short hairpin RNA-mediated interference technology, which was verified at both the mRNA and protein levels. Flow cytometry and TUNEL assay analysis indicated that ATF6 depletion decreased apoptosis and arrested the S phase of the cell cycle in mouse granulosa cells. Consistent with these results, ,, ,, ,, and mRNA expression decreased, whereas and mRNA expression increased. Interestingly, ATF6 knockdown obviously increased progesterone and estradiol production in mouse granulosa cells. () mRNA levels were downregulated, whereas ,, and mRNA levels were upregulated, in keeping with the changes in steroid hormones. Furthermore, ATF6 disruption remarkably increased () expression and decreased (), (), and () expression in mouse granulosa cells, which are proteins crucial for follicular development. But, after treating with tunicamycin, the levels of ,, and increased relatively, whereas expression decreased. Collectively, these results imply that ATF6, as a key player in ER stress signaling, may regulate apoptosis, the cell cycle, steroid hormone synthesis, and other modulators related to folliculogenesis in mouse granulosa cells, which may indirectly be involved in the development, ovulation, and atresia of ovarian follicles by affecting the physiological function of granulosa cells. The present study extends our understanding and provides new insights into the physiological significance of ATF6, a key signal transducer of ER stress, in ovarian granulosa cells.

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“…For example, overexpression of glucose-regulated protein 78 (GRP78), a heat shock protein upregulated during ER stress, in HEK-293 cells stably expressing FSHR, leads to decreased FSHR protein. 79 We observed an at least 20-fold increase in Grp78 levels in ER stress-induced GCs (data not shown), which could lead to decreased FSHR levels and decreased FSH response.…”

Section: Discussionmentioning

confidence: 72%

Cross-Talk Between FSH and Endoplasmic Reticulum Stress: A Mutually Suppressive Relationship

et al. 2016

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Suboptimal cellular conditions result in the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and trigger ER stress. In this study, we investigated the effects of follicle stimulating hormone (FSH) on ER stress in granulosa cells (GCs) obtained from 3-week-old female C57BL6 mice 24 or 48 hours after intraperitoneal injection of 5 IU pregnant mare's serum gonadotropin (PMSG), and in primary mouse GCs in culture treated with FSH (10-100 mIU/mL) for 24 or 48 hours. Moreover, mouse GCs in culture were treated with tunicamycin (Tm) or thapsigargin (Tp), which induce ER stress by inhibiting N-glycosylation of ER proteins and ER calcium adenosine triphosphatase, respectively, and their response to FSH was evaluated. We found that FSH attenuated ER stress in mouse GCs in vivo and in vitro; messenger RNA levels of ER stress-associated genes Xbp1s, Atf6, Chop, and Casp12 were decreased upon exposure to FSH/PMSG. Activating transcription factor 4 protein levels also demonstrated consistent decrease following FSH stimulation. Both Tm and Tp treatments inhibited FSH response, ER stressinduced cells did not show any change in estradiol levels in response to FSH, whereas in untreated GCs, estradiol production increased 3-fold after incubation with FSH for 60 hours. Furthermore, ER stress-induced cells failed to demonstrate aromatase (Cyp19a1) expression upon exposure to FSH. Importantly, under high-ER stress conditions FSH stimulation was unable to downregulate the expression of ER stress-associated genes. Our findings suggest that FSH decreases ER stress in GCs under physiologic conditions. However, under conditions that cause a significant increase in ER stress, FSH response is attenuated.

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Glucose-Regulated Protein, 78-Kilodalton Is a Modulator of Luteinizing Hormone Receptor Expression in Luteinizing Granulosa Cells in Rats1

Cited by 21 publications

References 35 publications

Effect of High Fat Dietary Intake during Maternal Gestation on Offspring Ovarian Health in a Pig Model

Effect of High Fat Dietary Intake during Maternal Gestation on Offspring Ovarian Health in a Pig Model

ATF6 knockdown decreases apoptosis, arrests the S phase of the cell cycle, and increases steroid hormone production in mouse granulosa cells

Cross-Talk Between FSH and Endoplasmic Reticulum Stress: A Mutually Suppressive Relationship

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