Role And Mechanism Of A1AT In Polycystic Ovary Syndrome

Polycystic ovary syndrome （PCOS）, one of the most common reproductive dysfunction in women, is an endocrine disorder which is frequently associated with metabolic dysfunction. The exact tiology and pathogenesis of PCOS keeplargely unknown. Studies have shown that pro-inflammatory cytokines play an important role in the pathogenesis of PCOS. Autoimmunity icould also be a important mechanism. Inflammatory theory has been very popular within PCOS feildin recent years, suggesting PCOS is also an inflammatory disease. Obesity as one of the common risk factors for both PCOS and metabolic diorders is closely associated with chronic inflammation. It has been shown that the adipose tissue is not only an energy storage tissue but also an highly active endocrinetissue. The pro-inflammatory cytokines secreted by adipose tissue inhibit anti-inflammatory cytokines and induce further secretion of pro-inflammatory cytokines, which play critical roles in PCOS.Our previous proteomic study has shown that circulating Alpha1-antitrypsin （A1AT） level declines in both obese population and PCOS patients.A1AT, an important serine protease inhibitor, is primarily synthesized in theliver. A1AT is widely found in serum of animals, and regulates the activity ofa variety of serine proteases. A1AT also protects normal cells and organs from acute phase inflammation, and maintains the balance in the organisms. Other cellsand tissues could also produce a small amount of A1AT, which plays a role in local tissue damage. Anti-inflammatory properties of human A1AT （hA1AT） has been widely reported in the clinical, however, its role in obesity and female r eproductive system keeps largely unclear. The obejective of this study is to evaluate the role of A1AT in obesity and obesity induced PCOS, therefore provide evidence fordevelopping a novel therapy for PCOS. Through the combination of clinical analysis, animal model establish and molecular mechanistic analysis, the present study demonstrated:（1） the difference of A1AT between lean and obese subjects. UtilizingELISA assays, we measured the serum A1AT, Leptin, Adiponectin, and insulin levels. Blood glucose levels were determined by glucose meter. SPSS wasused for the statistics. We showed that A1AT and Adiponectin are negativelycorrelated with body mass index （BMI）（P <0.05）, while Leptin showed a positive corretaltion with BMI, suggesting that obese subjects develop Leptin resistance and inturn affects A1AT levels.（2） the difference of A1AT levels between PCOS patients and normalcontrols. Using ELISA assays, we found that circulating A1AT levels decreasein PCOS patients compare to the control group. In addition, the pro-inflammatory cytokines IL-8, IL-1β were also significantly increased in PCOS patients,indicating that pro-inflammatory cytokines IL-8and IL-1β are negatively correlated with A1AT levels. We also shows an increased level of neutraophil elastase （NE）, one of the most important substrates of A1AT and the ratio of NE to A1AT in PCOS patients compare to normal subjects.（3） Effects of A1AT on PCOS Rats model. According to the clinicaldata we collected above, we speculate that A1AT maybe a potential treatmentof PCOS. To test this hypothesis, we established a rat PCOS model and treat them with A1AT. We observed that estrous cycle unchanged, anovulatory, ovarian morphology changed. As expected, A1AT treated group showed little changed in estrous cycle and ovarian morphology. These suggest that A1AT does play a role in PCOS and the injection of A1AT offer a protective effecton PCOS in rats.（4） Study the mechanism by which A1AT offer protective effects on PCOS in rats. Given the fact that the levels of pro-inflammatory cytokines IL8 and IL-1β increase in PCOS patients and A1AT treatment prevents PCOS inrats, we hypothesize that A1AT decreases the prevalence of PCOS through the inhibition of pro-inflammatory cytokines. By performing ELISA assays, weanalyzed the serum IL-8and IL-1β levels in PCOS control and A1AT treated PCOS rats and demonstrated that A1AT reduces the proinflammatory cytokines activity. Furthermore, we also found that A1AT significantly decreases theactivity of NE. These indicate that the effects of A1AT on PCOS is mediated through the anti-inflammatory and anti-NE activity properties.Through the successful accomplishment of the proposed studies, we demonstrated that A1AT is deficient in obesity and obesity induced PCOS patientsand restoration of A1AT levels in rat effectively prevents PCOS through thereduction of pro-inflammatory cytokines IL-8and IL-1β and inhibition of activity of NE. We speculate that obesity causes insulin resistance and Leptin resistance with in turn leads to the decreased section of A1AT in human. Thereduction of A1AT increased activity of neutrophil elastase, the major substrate of A1AT. The imbalance between NE activity and A1AT induces the secretion and accumulation of pro-inflammatory cytokines IL-8and IL-1β and leads to PCOS.Current therapeutic options for PCOS are non-surgical treatment, which makes clinical samples collection impossible. Thus, establish of the animal model of PCOS is a critical step for the basic and therapeutic research. In this article, we have successfully established a rat PCOS model by letrozole. Twenty days of IP injection of A1AT showed little changed in estrous cycle and ovarian morphology.。In summary, we identified that sirculating A1AT levels decline in both obesity and PCOS patients. We believe that the defiency of A1AT and imbalance of NE and A1AT trigger the accumulation of pro-inflammatory cytokines,such as IL-8and IL-1β, therefore leads to the pathogenesis of PCOS. The restoration of A1AT reverses PCOS in rat. These indicate that A1AT is optionor a potential therapeutic target for obesity and PCOS.