Apolipoprotein E Is a Putative Autocrine Regulator of the Rat Ovarian Theca Cell Compartment

Zerbinatti, Celina; Mayer, Loretta P.; Audet, Robert G.; Dyer, Cheryl A.

doi:10.1095/biolreprod64.4.1080

Cited by 18 publications

(11 citation statements)

References 49 publications

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“…This is in agreement with an earlier report from isolated theca/interstitial cells cultured from immature rats [23]. The combined in vivo and in vitro results reported here support the conclusion that VCD-induced follicle depletion results in an interstitial cell-enriched ovary that produces androgen in response to LH when insulin is also present.…”

Section: Discussionsupporting

confidence: 93%

“…Cells from these animals produced androstenedione, ranging from 10-13 ng/ml-g DNA per culture well, with no apparent sensitivity to LH. Interstitial cell androgen production is responsive to insulin [23]. Therefore, insulin was added to culture media to test its impact on progesterone and androstenedione production (Figs.…”

Section: Cell Culture Steroidogenic Productionmentioning

confidence: 99%

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The Follicle-Deplete Mouse Ovary Produces Androgen1

Mayer

Devine

Dyer

et al. 2004

Biology of Reproduction

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The follicle-depleted postmenopausal ovary is enriched in interstitial cells that produce androgens. This study was designed to cause follicle depletion in mice using the industrial chemical, 4-vinylcyclohexene diepoxide (VCD), and characterize the steroidogenic capacity of cells in the residual ovarian tissue. From a dose-finding study, the optimal daily concentration of VCD was determined to be 160 mg/kg. Female B6C3F(1) immature mice were treated daily with vehicle control or VCD (160 mg kg(-1) day(-1), 15 days, i.p.). Ovaries were removed and processed for histological evaluation. On Day 15 following onset of treatment, primordial follicles were depleted and primary follicles were reduced to about 10% of controls. On Day 46, primary follicles were depleted and secondary and antral follicles were reduced to 0.7% and 2.6% of control, respectively. Seventy-five percent of treated mice displayed disruptions in estrous cyclicity. All treated mice were in persistent diestrus (acyclic) by Day 58. Plasma FSH levels were increased (P < 0.05) relative to controls on Day 37 and had plateaued by Day 100. Relative to age-matched cyclic controls, by Day 127, the significant differences in VCD-treated mice included reduced ovarian and uterine weights, elevated plasma LH and FSH, and reduced plasma progesterone and androstenedione. Furthermore, plasma 17beta-estradiol levels were nondetectable. Unlike controls, immunostaining for LH receptor, and the high density lipoprotein receptor (SR-BI), was diffuse in ovarian sections from VCD-treated animals. Ovaries from Day 120 control and VCD-treated animals were dissociated and dispersed cells were placed in culture. Cultured cells from ovaries of VCD-treated animals produced less LH-stimulated progesterone than control cells. Androstenedione production was nondetectable in cells from cyclic control animals. Conversely, cells from VCD-treated animals produced androstenedione that was doubled in the presence of insulin and LH (1 and 3 ng/ml). Collectively, these data demonstrate that VCD-mediated follicle depletion results in residual ovarian tissue that may be analogous to the follicle-deplete postmenopausal ovary. This may serve as a useful animal model to examine the dynamics of follicle loss in women as ovarian senescence ensues.

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Section: Discussionsupporting

confidence: 93%

Section: Cell Culture Steroidogenic Productionmentioning

confidence: 99%

The Follicle-Deplete Mouse Ovary Produces Androgen1

Mayer

Devine

Dyer

et al. 2004

Biology of Reproduction

Self Cite

165

215

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“…Results of this study show for the first time that 1) LH stimulates Akt phosphorylation in cultured bovine theca cells, and that 2) activation of PI3K/Akt is involved in CYP17A1 mRNA expression and androgen production in theca cells. Reportedly, LH induced Akt phosphorylation in whole rat ovary [21], and the PI3K inhibitor, LY294002, suppressed androstenedione production by theca cells in rat [22] and cattle [11]. It is possible that LH-stimulated Akt phosphorylation in theca cells is responsible for these observations reported earlier.…”

Section: Discussionmentioning

confidence: 93%

Luteinizing hormone-induced Akt phosphorylation and androgen production are modulated by MAP Kinase in bovine theca cells

et al. 2009

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BackgroundTheca cells play an important role in controlling ovarian steroidogenesis by providing aromatizable androgens for granulosa cell estrogen biosynthesis. Although it is well established that the steroidogenic activity of theca cells is mainly regulated by LH, the intracellular signal transduction mechanisms that regulate thecal proliferation and/or steroidogenesis remain obscure. In this study, we examined whether and how LH controls the PI3K/Akt signaling pathway and androgen production in bovine theca cells. We also explored whether this LH-induced PI3K/Akt activation is modulated with other signaling pathways (i.e. PKA and MAPK).MethodsOvarian theca cells were isolated from bovine small antral follicles and were incubated with LH for various durations. Phospho-Akt and total-Akt content in the cultured theca cells were examined using Western blotting. Androstenedione levels in the spent media were determined using EIA. Semi-quantitative RT-PCR analyses were conducted to analyze the mRNA levels of CYP17A1 and StAR in the theca cells. To examine whether Akt activity is involved in theca cell androgen production, the PI3K inhibitors wortmannin and LY294002 were also added to the cells.ResultsAkt is constitutively expressed, but is gradually phosphorylated in cultured bovine theca cells through exposure to LH. LH significantly increased androstenedione production in bovine theca cells, whereas addition of the wortmannin and LY294002 significantly decreased LH-induced androstenedione production. LH significantly increased CYP17A1 mRNA level in theca cells, whereas addition of LY294002 significantly decreased LH-induced CYP17A1 expression. Neither LH nor PI3K inhibitors alter the mRNA levels of StAR in theca cells. Although H89 (a selective inhibitor of PKA) does not affect LH-mediated changes in Akt, U0126 (a potent MEK inhibitor) suppressed LH-induced Akt phosphorylation, CYP17A1 expression, and androgen production in theca cells.ConclusionThese results indicate that LH stimulates CYP17 mRNA expression and androgen production in theca cells via activation of the PI3K/Akt pathway. The LH-induced Akt phosphorylation and androgen production are modulated by the MAPK signaling in bovine theca cells.

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“…These results indicate that the deletion of Apoe has an obvious influence on ovarian follicle development. Previous studies have demonstrated that intraovarian APOE can control the production of 148 T Zhang, P Dai and others androgen in theca cells (Zerbinatti et al 2001). Therefore, the level of androgens in the Apoe K/K mice may exceed that in the WT mice.…”

Section: Discussionmentioning

confidence: 99%

Obesity occurring in apolipoprotein E-knockout mice has mild effects on fertility

et al. 2014

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The Apolipoprotein (Apo) family is implicated in lipid metabolism. There are five types of Apo: Apoa, Apob, Apoc, Apod, and Apoe. Apoe has been demonstrated to play a central role in lipoprotein metabolism and to be essential for efficient receptor-mediated plasma clearance of chylomicron remnants and VLDL remnant particles by the liver. Apoe-deficient (Apoe K/K ) mice develop atherosclerotic plaques spontaneously, followed by obesity. In this study, we investigated whether lipid deposition caused by Apoe knockout affects reproduction in female mice. The results demonstrated that Apoe K/K mice were severely hypercholesterolemic, with their cholesterol metabolism disordered, and lipid accumulating in the ovaries causing the ovaries to be heavier compared with the WT counterparts. In addition, estrogen and progesterone decreased significantly at D 100. Quantitative PCR analysis demonstrated that at D 100 the expression of cytochromeP450 aromatase (Cyp19a1), 3b-hydroxysteroid dehydrogenase (Hsd3b), mechanistic target of rapamycin (Mtor), and nuclear factor-kB (Nfkb) decreased significantly, while that of BCL2-associated agonist of cell death (Bad) and tuberous sclerosis complex 2 (Tsc2) increased significantly in the Apoe K/K mice. However, there was no difference in the fertility rates of the Apoe K/K and WT mice; that is, obesity induced by Apoe knockout has no significant effect on reproduction. However, the deletion of Apoe increased the number of ovarian follicles and the ratio of ovarian follicle atresia and apoptosis. We believe that this work will augment our understanding of the role of Apoe in reproduction.

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Apolipoprotein E Is a Putative Autocrine Regulator of the Rat Ovarian Theca Cell Compartment

Cited by 18 publications

References 49 publications

The Follicle-Deplete Mouse Ovary Produces Androgen1

The Follicle-Deplete Mouse Ovary Produces Androgen1

Luteinizing hormone-induced Akt phosphorylation and androgen production are modulated by MAP Kinase in bovine theca cells

Obesity occurring in apolipoprotein E-knockout mice has mild effects on fertility

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