Bernardo, Tiffany M
(2020)
Roles of PPARγ and Lactate Metabolism in The Hypoxic Response of Trophoblasts.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
Normal placental development and function is critical for the viability and growth of the developing embryo. Oxygen gradients are a key determinant in normal placental development, as evidenced by the severe defects in placentas deficient for the transcription factor Hypoxia-Inducible Factor α (Hif1a) and its regulators. Additionally, aberrant oxygenation is a frequent driver of placental pathologies, including intrauterine growth restriction and preeclampsia. Placentas deficient for the nuclear receptor Peroxisome Proliferator-Activated Receptor γ (Pparg) exhibit severe, lethal vascular defects that strongly resemble those in knockouts of HIF1α pathway genes. This dissertation establishes that PPARγ is essential for sustained HIF1α activation and survival of trophoblasts during acute hypoxic exposure. Hypoxia necessitates a switch from aerobic respiration to glycolytic metabolism, which is largely mediated by HIF1α target genes, augmenting lactate synthesis. Importantly, placental PPARγ strongly regulates Lactate Dehydrogenase B (Ldhb) and Pyruvate Carboxylase (Pcx), two enzymes whose tandem action converts lactate to oxaloacetate. Metabolomic profiling revealed significantly elevated levels of both L-lactate and pyruvate in PPARγ-null trophoblast stem cells cultured under acute hypoxic conditions. Moreover, pharmacological manipulation of anaerobic glycolysis inhibited the sustained activation of HIF1α, PPARγ and additional downstream proteins in hypoxic trophoblast cultures. Stable human trophoblast cell lines engineered to lack key hypoxia regulatory proteins were used to further delineate the PPARγ-HIF1α axis. In vivo, analyses of the effect of Ldhb deficiency on vascular development of placentas subject to hypoxic stress found that whereas Ldhb-null and WT placentas are grossly similar in normoxic pregnancies, Ldhb deficiency ameliorated vascular anomalies in placentas from hypoxic pregnancies. These data implicate PPARγ as a crucial player in the hypoxic adaptation of trophoblasts. We further hypothesize that PPARγ regulates the HIF1α axis, in part, by controlling the intracellular levels of lactate and its metabolites.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
6 February 2020 |
| Date Type: |
Publication |
| Defense Date: |
18 December 2019 |
| Approval Date: |
6 February 2020 |
| Submission Date: |
10 January 2020 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
113 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cellular and Molecular Pathology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Trophoblast, Hypoxia, PPARγ, Lactate, Metabolism, Placenta |
| Date Deposited: |
06 Feb 2020 20:39 |
| Last Modified: |
06 Feb 2020 20:39 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/38124 |
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