ABSTRACT
Intra-ovarian local factors regulate the follicular microenvironment in coordination with gonadotrophins, thus playing a crucial role in ovarian physiology as well as pathological states such as polycystic ovary syndrome (PCOS). One recently recognized local factor is endoplasmic reticulum (ER) stress, which involves the accumulation of unfolded or misfolded proteins in the ER related to various physiological and pathological conditions that increase the demand for protein folding or attenuate the protein-folding capacity of the organelle. ER stress results in activation of several signal transduction cascades, collectively termed the unfolded protein response (UPR), which affect a wide variety of cellular functions. Recent studies have revealed diverse roles of ER stress in physiological and pathological conditions in the ovary. In this review, we summarize the most current knowledge of the regulatory roles of ER stress in the ovary, in the context of reproduction. The physiological roles of ER stress and the UPR in the ovary remain largely undetermined. On the contrary, activation of ER stress is known to impair follicular and oocyte health in various pathological conditions; moreover, ER stress also contributes to the pathogenesis of several ovarian diseases, including PCOS. Finally, we discuss the potential of ER stress as a novel therapeutic target. Inhibition of ER stress or UPR activation, by treatment with existing chemical chaperones, lifestyle intervention, or the development of small molecules that target the UPR, represents a promising therapeutic strategy.
Subject(s)
Endoplasmic Reticulum Stress , Endoplasmic Reticulum/physiology , Ovary/physiology , Animals , Cellular Microenvironment , Female , Humans , Ovarian Diseases/physiopathology , Unfolded Protein ResponseABSTRACT
Recent studies have uncovered the critical role of aryl hydrocarbon receptor (AHR) in various diseases, including obesity and cancer progression, independent of its previously identified role as a receptor for endocrine-disrupting chemicals (EDCs). We previously showed that endoplasmic reticulum (ER) stress, a newly recognized local factor in the follicular microenvironment, is activated in granulosa cells from patients with polycystic ovary syndrome (PCOS) and a mouse model of the disease. By affecting diverse functions of granulosa cells, ER stress contributes to PCOS pathology. We hypothesized that expression of AHR and activation of its downstream signaling were upregulated by ER stress in granulosa cells, irrespective of the presence of EDCs, thereby promoting PCOS pathogenesis. In this study, we found that AHR, AHR nuclear translocator (ARNT), and AHR target gene cytochrome P450 1B1 (CYP1B1) were upregulated in the granulosa cells of PCOS patients and model mice. We examined CYP1B1 as a representative AHR target gene. AHR and ARNT were upregulated by ER stress in human granulosa-lutein cells (GLCs), resulting in an increase in the expression and activity of CYP1B1. Administration of the AHR antagonist CH223191 to PCOS mice restored estrous cycling and decreased the number of atretic antral follicles, concomitant with downregulation of AHR and CYP1B1 in granulosa cells. Taken together, our findings indicate that AHR activated by ER stress in the follicular microenvironment contributes to PCOS pathology, and that AHR represents a novel therapeutic target for PCOS.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Endoplasmic Reticulum Stress , Granulosa Cells/metabolism , Polycystic Ovary Syndrome/metabolism , Receptors, Aryl Hydrocarbon/metabolism , Adult , Animals , Aryl Hydrocarbon Receptor Nuclear Translocator/metabolism , Azo Compounds/pharmacology , Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors , Basic Helix-Loop-Helix Transcription Factors/genetics , Case-Control Studies , Cells, Cultured , Cytochrome P-450 CYP1B1/metabolism , Disease Models, Animal , Estrous Cycle/metabolism , Female , Granulosa Cells/drug effects , Granulosa Cells/pathology , Humans , Mice, Inbred BALB C , Middle Aged , Polycystic Ovary Syndrome/drug therapy , Polycystic Ovary Syndrome/genetics , Polycystic Ovary Syndrome/pathology , Pyrazoles/pharmacology , Receptors, Aryl Hydrocarbon/antagonists & inhibitors , Receptors, Aryl Hydrocarbon/genetics , Signal Transduction , Up-Regulation , Young AdultABSTRACT
Recent studies report the involvement of intra-ovarian factors, such as inflammation and oxidative stress, in the pathophysiology of polycystic ovary syndrome (PCOS), the most common endocrine disorder of reproductive age women. Endoplasmic reticulum (ER) stress is a local factor that affects various cellular events during a broad spectrum of physiological and pathological conditions. It may also be an important determinant of pro-fibrotic remodeling during tissue fibrosis. In the present study, we showed that ER stress was activated in granulosa cells of PCOS patients as well as in a well-established PCOS mouse model. Pharmacological inducers of ER stress, tunicamycin and thapsigargin, were found to increase the expression of pro-fibrotic growth factors, including transforming growth factor (TGF)-ß1, in human granulosa cells, and their expression also increased in granulosa cells of PCOS patients. By contrast, treatment of PCOS mice with an ER stress inhibitor, tauroursodeoxycholic acid or BGP-15, decreased interstitial fibrosis and collagen deposition in ovaries, accompanied by a reduction in TGF-ß1 expression in granulosa cells. These findings suggest that ER stress in granulosa cells of women with PCOS contributes to the induction of pro-fibrotic growth factors during ovarian fibrosis, and that ER stress may serve as a therapeutic target in PCOS.
