Ihunnah, Chibueze
(2014)
The Role of Estrogen Sulfotransferase in Human Adipogenesis.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Estrogen Sulfotransferase (EST/SULT1E1) is a phase II conjugating enzyme which catalyzes the sulfonation of estrogen and estrogen like compounds. EST belongs to a large class of cytosolic sulfotransferases that are widespread in human and animal tissues, and facilitate sulfoconjugation through a donor co-substrate, 3′-phosphoadenosine 5′-phosphosulfate (PAPS). EST is an estrogen preferring sulfotransferase; among all human sulfotransferases it has the highest affinity for Estradiol (E2).
The goal of this dissertation is to determine whether and how EST plays a role in human adipogenesis. Adipogenesis is the process whereby preadipocytes are stimulated to differentiate into functional mature adipocytes. The role of EST in adipogenesis has been studied in rodents, however in humans no studies have been published that address the role of EST in adipogenesis. In this dissertation we have uncovered a novel role for estrogen sulfotransferase in human adipogenesis. By using human primary adipose-derived stem cells (ASCs) and whole-fat tissues from the abdominal subcutaneous fat of obese and non-obese subjects, we showed that the expression of EST was low in preadipocytes but increased upon differentiation. Overexpression and knockdown of EST in ASCs promoted and inhibited differentiation, respectively. The pro-adipogenic activity of EST in humans was opposite to the anti-adipogenic effect of the same enzyme in rodents. Mechanistically, EST promoted adipogenesis by deactivating estrogens. The pro-adipogenic effect of EST can be recapitulated by using an estrogen receptor (ER) antagonist or ER alpha knockdown. In contrast, activation of ER in ASCs inhibited adipogenesis by decreasing the recruitment of the adipogenic peroxisome proliferator-activated receptor gamma (PPAR) onto its target gene promoters, whereas ER antagonism increased the recruitment of PPAR to its target gene promoters. Linear regression analysis revealed a positive correlation between the expression of EST and body mass index (BMI), as well as a negative correlation between ER alpha expression and BMI. We conclude that EST is a pro-adipogenic factor which may serve as a druggable target to inhibit the turnover and accumulation of adipocytes in obese patients.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
5 August 2014 |
| Date Type: |
Publication |
| Defense Date: |
30 May 2014 |
| Approval Date: |
5 August 2014 |
| Submission Date: |
28 July 2014 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
142 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Estrogen Sulfotransferase |
| Date Deposited: |
05 Aug 2014 13:37 |
| Last Modified: |
05 Aug 2019 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/22536 |
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