Bezafibrate Restores the Inhibition of FSH-Induced Follicular Development and Steroidogenesis by Tumor Necrosis Factor-Alpha Through Peroxisome Proliferator-Activated Receptor-Gamma Pathway in an In Vitro Mouse Preantral Follicle Culture
Bezafibrate Restores the Inhibition of FSH-Induced Follicular Development and Steroidogenesis by Tumor Necrosis Factor-Alpha Through Peroxisome Proliferator-Activated Receptor-Gamma Pathway in an In Vitro Mouse Preantral Follicle Culture
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DOI：
10.1095/biolreprod.111.090738
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发表时间：
2011-11-01
影响因子：
3.6
通讯作者：
Kurachi, Hirohisa
中科院分区：
文献类型：
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作者：
Hara, Shuichiro;Takahashi, Toshifumi;Kurachi, Hirohisa
我们最近报道了贝扎贝特，一种贝扎贝特类降脂药物，与枸橼酸克罗米芬（CC）一起使用，成功地诱导了耐CC多囊卵巢综合征（PCOS）患者的排卵。我们假设贝扎布特可能直接影响卵巢卵泡发育。胰岛素抵抗和代偿性高胰岛素血症是多囊卵巢综合征的重要发病机制。在本研究中，我们首先通过卵泡培养系统检测了在胰岛素抵抗中起作用的肿瘤坏死因子- α (TNF)对卵泡发育的影响。TNF显著抑制促卵泡激素（FSH）诱导的卵泡发育、17 -雌二醇（E2）分泌和排卵率呈剂量依赖性。然后，我们研究了贝扎布特治疗是否可以挽救fsh诱导的卵泡发育和TNF的类固醇生成的抑制。贝扎布特治疗挽救了卵泡发育、E2分泌和TNF排卵率的抑制作用。我们检测了小鼠窦前卵泡中过氧化物酶体增殖物激活受体（PPAR）亚型的表达。由于在小鼠腔前卵泡中只观察到PPARG的蛋白表达，我们研究了贝扎布特是否可以通过PPARG通路影响卵泡发育和甾体生成。GW1929（一种选择性PPARG激动剂）治疗恢复了fsh诱导的卵泡发育和TNF对类固醇生成的抑制作用，而GW9662（一种选择性PPARG拮抗剂）治疗则取消了贝扎布特的恢复作用。综上所述，本研究的结果表明，贝扎布特可能通过PPARG途径直接对TNF对卵巢卵泡发育和类固醇生成的抑制表现出恢复作用。
We recently reported that bezafibrate, a lipid-lowering drug of the fibrate class, administered in addition to clomiphene citrate (CC) successfully induced ovulation in CC-resistant polycystic ovary syndrome (PCOS) patients. We hypothesized that bezafibrate may directly affect ovarian follicle development. Insulin resistance and compensatory hyperinsulinemia are important for the pathogenesis of PCOS. In this study, we first examined the effects of tumor necrosis factor-alpha (TNF), which plays a role in insulin resistance, on follicle development by using the follicle culture system. TNF significantly inhibited follicle-stimulating hormone (FSH)-induced follicle development, 17beta-estradiol (E2) secretion, and ovulation rate in a dose-dependent manner. We then examined whether bezafibrate treatment could rescue the inhibition of FSH-induced follicle development and steroidogenesis by TNF. Bezafibrate treatment rescued inhibition of follicle development, secretion of E2, and ovulation rate by TNF. We examined the expression of peroxisome proliferator-activated receptor (PPAR) subtypes in mouse preantral follicles. As the protein expression of only PPARG was observed in mouse preantral follicles, we examined whether bezafibrate could affect follicle development and steroidogenesis through PPARG pathways. Treatment with GW1929, a selective PPARG agonist, restored inhibition of FSH-induced follicle development and steroidogenesis by TNF, whereas treatment with GW9662, a selective PPARG antagonist, canceled the restorative effects of bezafibrate. Collectively, the results in this study suggest that bezafibrate may directly exhibit a restorative effect on the inhibition of ovarian follicle development and steroidogenesis by TNF through the PPARG pathway.