Peroxisome proliferator activated receptor ligands: novel tools to enhance ART/IVF success
醫師，給我藥，吃了可以改善胚胎品質！
Peroxisome proliferator activated receptor ligands: novel tools to enhance ART/IVF success
In several species, a family of nuclear receptors, the peroxisome proliferator-activated receptors (PPARs) composed of three isotypes, is expressed in somatic cells and germ cells of the ovary as well as the testis. Invalidation of these receptors in mice or stimulation of these receptors in vivo or in vitro showed that each receptor has physiological roles in the gamete maturation or the embryo development. In addition, synthetic PPARγ ligands are recently used to induce ovulation in women with polycystic ovary disease. These results reveal the positive actions of PPAR in reproduction. This review will summarize the current knowledge on the expression and the function of PPARs in the gametes and the preimplantation embryos. The effects of natural and synthetic PPAR ligands on gamete function and embryo development as well as their potential application in ART/IVF will be discussed.
，發表一份PPAR的研究，雖然引用很多動物實驗的數據，
做試管嬰兒的病人感覺壓力最大就是也取卵了，
但植入胚胎當天，醫師告訴她「很抱歉！胚胎的品質不理想、
都還沒有胚胎植入子宮病人就已經給這句話給打敗、打的"頭破血流
在下一個問題恐怕你最想問的就是
:「好了，胚胎的品質不好，醫師，你給我藥，
的確，胚胎的品質不好，是可以理解的，但是，
查據文獻，最近有一個新藥物可以改善胚胎的品質，
就是台語的"會吐啦"，Astose叫做"愛妥糖"，
為什麼這個藥物可以改善胚胎的品質，在卵子形成的過程當中LH是
但是LH太高又會影響胚胎的品質，
最近有一--國內某醫院--研究顯示；在7個不孕症的病人做過試
但有3個流產，4個活產，
即使試管嬰兒試過這個藥物之後，有4個活產3個流產，
更誇張的成績是：最近有一國內某醫院研究顯示；針對45歲以上;
所以你問我有什麼藥物可以改善胚胎的品質，我會告訴妳:Acto
因此，吃藥當中記得每個月測量肝功能，若肝功能指數超過34就需
博元婦產科全體同仁祝
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The Potential Applications of Peroxisome Proliferator-Activated Receptor δ Ligands in Assisted Reproductive Technology Jaou-Chen Huang* Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology & Reproductive Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030, USA *Jaou-Chen Huang: Email: jaou-chen.huang@uth. Recommended by Francine M. Gregoire Received May 13, 2008; Revised June 27, 2008; Accepted September 12, 2008. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
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3. BIOLOGICAL FUNCTIONS OF PPARδ |
Abstract Peroxisome proliferator-activated receptor δ (PPARδ, also known as PPARβ) has ubiquitous distribution and extensive biological functions. The reproductive function of PPARδ was first revealed in the uterus at the implantation site. Since then, PPARδ and its ligand have been discovered in all reproductive tissues, including the gametes and the preimplantation embryos. PPARδ in preimplantation embryos is normally activated by oviduct-derived PPARδ ligand. PPARδ activation is associated with an increase in embryonic cell proliferation and a decrease in programmed cell death (apoptosis). On the other hand, the role of PPARδ and its ligand in gamete formation and function is less well understood. This review will summarize the reproductive functions of PPARδ and project its potential applications in assisted reproductive technology. |
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3. BIOLOGICAL FUNCTIONS OF PPARδ |
1. INTRODUCTION Assisted reproduction uses a spectrum of technologies to enhance fertility. In vitro fertilization (IVF) is the most advanced and most sophisticated assisted reproductive technology (ART). Since the first "IVF baby", Louise Brown, was born in 1978, IVF has gradually been accepted by the general public. Nowadays, IVF is a routine procedure to treat the infertile couples. Recent data shows more than 45 000 IVF babies were born in the US each year (http://www.cdc.gov/ART/ Compared with embryos in natural pregnancies, IVF embryos have low implantation potential (about 15–20% per embryo, http://apps.nccd.cdc. It has long been observed that, compared with in vivo embryos, embryos cultured in simple media develop at a slower pace [1, 2] and have more apoptosis [3]. It is generally accepted that, compared with in vivo embryos, IVF embryos are in a less optimal environment—they are not in the supportive and protective environment of the oviduct. As a result, IVF embryos do not develop to their full potential and do not implant as well as their in vivo counterparts. It has been proposed that modifying embryo culture conditions, making them similar to those of the oviduct, may improve embryo development and enhance IVF success. Recent reports show embryos express PPARδ and that PPARδ activation by oviduct-derived ligand enhances embryo development and implantation (more below). Thus PPARδ is a novel pathway that could be exploited to enhance ART outcome. This article will review the current literature regarding PPARδ and reproduction and outline the potential applications of its ligands in ART. Because PPARδ interacts with PPARα and -γ, relevant information regarding PPARα and -γwill also be provided. |
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3. BIOLOGICAL FUNCTIONS OF PPARδ |
2. PPARS AND THEIR LIGANDS Peroxisomes are organelles in eukaryotes that participate in fatty acid oxidation. In 1990, the first PPAR (PPARα) was discovered in the mouse [4]. Two years later, PPARα and two additional PPAR isotypes, PPARβ (also known as PPARδ) and PPARγ, were discovered in the Xenopus [5]. Subsequently, all three isotypes were found in mouse and many species including human. PPARδ was originally discovered in a human osteosarcoma cell line [6] and later found to be the human homolog of PPARβ in the Xenopus. PPARs are ligand-activated transcription factors. They form heterodimers with another nuclear receptor, retinoid X receptor (RXR), which also has three isotypes: RXRα, β, and γ [7]. The functions of PPAR-RXR complexes are determined by PPAR isotypes. Although either PPAR or RXR ligand can activate PPAR-RXR complexes, simultaneous PPAR and RXR binding yields more potent activities [8]. Whereas PPARα and PPARγ activate genes related to glucose and lipid metabolism, only a few genes are reported to be directly regulated by PPARδ. PPARδ reportedly upregulates PDK1, ILK [9] and 14-3-3ε [10], and downregulates PTEN [9] and 11 beta hydroxysteroid dehydrogenase type 2 gene [11]. The functions of these genes, unlike those regulated by PPARα and PPARγ, are not limited to energy homeostasis. They include carbohydrate homeostasis (PDK1), cell migration, proliferation and adhesions (ILK), signal transduction (ILK) and its modulation (14-3-3ε) and, finally, tumor suppression (PTEN). Unlike PPARα and PPARγ, the outcome of PPARδ activation is not limited to the transcriptional activities of genes directly regulated by PPARδ because PPARδ also modulates the transcriptional activities of PPARα, PPARγ, other nuclear receptors (such as estrogen receptor), and BCL-6 (a transcriptional repressor). A recent report shows that binding of PPARδ by its ligand allows full transcriptional activities of PPARα and PPARγ, which is normally inhibited by nonliganded PPARδ [12]. In addition, binding of PPARδ by its ligand releases a transcription repressor BCL-6 [13] which targets a group of genes with diverse activities including transcription regulation (n = 18), protein binding (n = 11), signal transduction (n = 10), catalysis (n = 8), structural molecule activity (n = 3), enzyme activity regulation (n = 3), protein transportation (n = 2), cell movement (n = 2), chaperone (n = 1), and unknown function (n = 3) [14]. Thus PPARδ interacts with an extensive array of intracellular proteins to regulate cellular functions. A diverse group of chemicals including hypolipidemic drugs, herbicides, and industrial plasticizers causes liver tumors in the rodents. They induce peroxisome proliferation and led to the discovery of PPARα [4]. Fatty acids, particularly the unsaturated fatty acids, and certain eicosanoids bind to PPARα, -γ, and -δ with varying affinities [8, 15]. Although all PPAR isotypes bind to unsaturated fatty acids, PPARα has the highest affinity. Eicosanoids from the lipoxygenase pathway (such as leukotrienes and hydroxyeicosatetraenoic acids—HETEs) and the cyclooxygenase pathway (such as prostaglandins—PGs) bind to PPARs: leukotriene B4 and 8(S)-HETE are PPARα ligand, 15-deoxy-Δ12,14-PGJ2 (a PGD2 derivative) is a PPARγligand, and PGI2 is a PPARδ ligand [15]. In addition to the natural ligands, PPARs also respond to synthetic ligands. Some of the synthetic PPAR ligands are currently used to treat metabolic diseases: fibrates, which bind to PPARα, are hypolipidemic agents; thiazolidinediones (TZDs), which bind to PPARγ, are insulin sensitizers. A recent report shows that retinoic acid, depending on the ratio of cellular retinoic acid binding protein 2 (CRABP-II) and fatty acid binding protein 5 (FABP5), may function as a PPARδ ligand [16]. |
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3. BIOLOGICAL FUNCTIONS OF PPARδ The roles of PPARα and PPARγ in energy homeostasis are relatively easy to understand because the former is predominantly expressed in the brown adipose tissue and liver, and the latter, the adipose tissue [8, 17]. While PPARα catabolizes lipid in the liver, PPARγ facilitates fatty acid storage in adipose tissue by inducing the maturation of preadipocyte to fat cells. The functions of PPARδ, on the other hand, are not as easy to ascertain because PPARδ has a ubiquitous distribution (including high levels of expression in the gut, kidney, and heart, and a lower level of expression in the liver) and interacts with extensive arrays of proteins in the cells (more in Section 2). Reported functions of PPARδ include the formation of intestinal adenoma [18] and colon cancer [19], the healing of skin [20], the development of hair follicles [21], and the protection of cells against noxious stimuli [10, 22]. The reproductive function of PPARδ was revealed for the first time during the investigation of cyclooxygenase-2 knockout mouse [23]. |
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3. BIOLOGICAL FUNCTIONS OF PPARδ |
4. PPARδ AND REPRODUCTION In primates, including humans, mature eggs are picked up by the fimbria and become fertilized in the ampulla. The zygotes remain in the oviduct for 72 hours; develop to morula/early blastocyst stage embryos before entering into the uterus. During this period, the oviduct produces soluble factors to promote embryo development and protect the embryo. As mentioned earlier, the link between PPARδ and reproduction was first revealed at the implantation site of cyclooxygenase-2 knock out mice [23]. Since then, it was learned that embryos express PPARδ and that oviducts and embryos produce PGI2. Recent studies also show that exogenous PPARδ ligand promotes the development of embryos and enhances their implantation potential (more in Section 4.4). 4.1. Female reproductive tract and embryos produce PPARδ ligand We analyzed the metabolites of arachidonic acid by human [24] and mouse [25] oviducts and found substantial amount of PGI2. Further analysis shows that PGI2 production by the oviducts varies according to the estrus cycle. It peaks shortly after ovulation, coincides with the presence of cleaving zygotes in the oviduct and the "window" of embryonic responsiveness to PGI2 [25]. Oviducts posses PGI2 synthase and cyclooxygenase-2; the latter is the rate limiting enzyme of PG synthesis. The increased PGI2 production is due to upregulation of the cyclooxygenase-2 gene. Oviduct also produces retinoic acid [26], the effects of oviduct-derived retinoic acid on embryo development is controversial (details below). Similar to oviducts, embryos also metabolize arachidonic acid via cyclooxygenase and lipoxygenase pathways. PGI2 is the most abundant metabolites of arachidonic acid by mouse embryos [27]. Preimplantation embryos express PGI2 synthase, and cyclooxygenase-1 and -2; all are expressed in early stage and throughout the preimplantation period. The preimplantation embryos also produce retinoic acid [28] but its role in embryo development is yet to be determined. The uterus is known to produce PGI2 [29] but its central role in assisting embryo implantation was not revealed until twenty years later [23]. The uterus produces retinoic acid [30] but its biological role is unclear. Similarly, the ovary produces retinoic acid [31] and PGI2 [32] but the extent to which they interact with PPARδ to influence oocyte maturation is not clear. 4.2. Testes express PPARδ All three PPAR isotypes are present in Sertoli and Leydig cells of the testes: PPARα and -δtranscript and protein are expressed in Leydig cells and Sertoli cells of rat [33], PPARγ1 transcript is detected in human testis [34], both PPARα and -γ transcripts and proteins are expressed in mouse Sertoli cells [35]. In addition, mouse spermatids and spermatocytes express PPARδ [36]. The functionality of PPARδ in the testes is supported by the presence ofSsm, a novel PPARδ target gene in mouse testes [37]. Thus PPARδ may directly or indirectly (i.e., via PPARα or -γ) affect spermatogenesis. Information regarding PPARδ expression and action in mature sperms is limited. We previously report that iloprost (a PGI2 analog) does not affect sperm activity [38]. However, the response of mature sperms to synthetic PPARδ ligand or retinoic acid has not been reported. 4.3. Ovaries express PPARδ Similar to testes, the ovary expresses all three PPAR isotypes [39]. While PPARδ is expressed throughout the ovary, PPARα is mainly expressed in the theca and the stroma, and PPARγ, in the granulosa cells (of human, pig, rodents, and sheep) and the oocytes (of cattle and zebrafish). Of the three PPAR isotypes in the ovary, only PPARγ shows cyclic changes thus implying its role in follicular genesis and/or oocyte maturation. Since PPARδ may regulate the transcriptional activity of PPARγ, the growth of follicles or oocytes may be indirectly modulated by PPARδ ligand. The expression of PPARδ and the effect of its activation on the oocytes remain unclear at the moment. 4.4. Preimplantation embryos express PPARδ Compared with PPARγ [28, 40] or PPARα [28, 40], there is more information regarding the expression of PPARδ and the outcome of its activation on preimplantation embryos [28, 40]. Mouse embryos express PPARδ at an early stage [40, 41] and throughout the preimplantation period. Blastocyst stage embryos express PPARδ in the inner cell mass and the trophectoderm [40]. PPARδ activation is associated with embryonic cell proliferation and improved embryo development [40]. Supplementing L-165,041 (a synthetic PPARδ ligand) or iloprost (a PGI2 |
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