Abstract
During pregnancy crucial anatomic, physiologic, and metabolic changes challenge the mother and the fetus. The placenta is a remarkable organ that allows the mother and the fetus to adapt to the new metabolic, immunologic, and angiogenic environment imposed by gestation. One of the physiologic systems that appears to have evolved to sustain this metabolic regulation is mediated by peroxisome proliferator-activated receptors (PPARs). In clinical pregnancy-specific disorders, including preeclampsia, gestational diabetes, and intrauterine growth restriction, aberrant regulation of components of the PPAR system parallels dysregulation of metabolism, inflammation and angiogenesis. This review summarizes current knowledge on the role of PPARs in regulating human trophoblast invasion, early placental development, and also in the physiology of clinical pregnancy and its complications. As increasingly indicated in the literature, pregnancy disorders, such as preeclampsia and gestational diabetes, represent potential targets for treatment with PPAR ligands. With the advent of more specific PPAR agonists that exhibit efficacy in ameliorating metabolic, inflammatory, and angiogenic disturbances, further studies of their application in pregnancy-related diseases are warranted.
Highlights
Peroxisome proliferator-activated receptors (PPARs) are major regulators of lipid and glucose metabolism, inflammation, and angiogenesis [1,2,3,4,5,6] that allow adaptation of the mother to the nutritional and perfusion requirements of the fetus [3, 7, 8]
A number of naturally-occurring PPAR ligands have been identified, including long-chain fatty acids (C16 and greater), eicosanoids such as 8(S)-HETE (PPARα) and 9and13-HODE (PPARγ), and PGs such as PGA1,which binds to PPARα, PPARβ/δ, and 15-deoxy-delta12,14-prostaglandin J2(15dPGJ2), which in turn binds to PPARγ [70,71,72]
The focus of this review is to summarize findings on PPAR/RXR heterodimers in human placentation, much of the direct evidence for a role of these receptors in trophoblast invasion and placental development has emerged from studies in knockout mouse models
Summary
Peroxisome proliferator-activated receptors (PPARs) are major regulators of lipid and glucose metabolism, inflammation, and angiogenesis [1,2,3,4,5,6] that allow adaptation of the mother to the nutritional and perfusion requirements of the fetus [3, 7, 8]. A number of naturally-occurring PPAR ligands have been identified, including long-chain fatty acids (C16 and greater), eicosanoids such as 8(S)-HETE (PPARα) and 9and13-HODE (PPARγ), and PGs such as PGA1,which binds to PPARα, PPARβ/δ, and 15-deoxy-delta12,14-prostaglandin J2(15dPGJ2), which in turn binds to PPARγ [70,71,72]. Both the expression of PPAR and the production of their potential ligands are altered during pregnancy and its related diseases. We postulate that pathologic diversion of fatty-acid metabolism away from the production of eicosanoid ligands in preeclampsia and gestational diabetes might be corrected using synthetic ligands
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