THE ANDROGEN DEPENDENT AND INDEPENDENT ROLES OF INSULIN-INDUCED AKR1C3 IN A MODEL OF POLYCYSTIC OVARY SYNDROME ADIPOCYTES

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Degree type
Doctor of Philosophy (PhD)
Graduate group
Pharmacology
Discipline
Pharmacology, Toxicology and Environmental Health
Medical Sciences
Biochemistry, Biophysics, and Structural Biology
Subject
Adipocyte Biology
Androgen Excess
Insulin Signaling
Polycystic Ovary Syndrome
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2023
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Paulukinas, Ryan
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Abstract

Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy in women of reproductive age. In PCOS, hyperandrogenism and insulin resistance could promote cardio-metabolic comorbidities. One dominant enzyme involved in peripheral androgen biosynthesis and induced by insulin is aldo-keto reductase family 1 member C3 (AKR1C3). The 11-oxygenated androgens have been recently identified as the predominant androgens in the serum of PCOS patients and are metabolized by AKR1C3. Fatty acid synthase (FASN) is induced by androgens and is the central enzyme for de novo lipogenesis. We hypothesize that insulin induction of AKR1C3 in PCOS adipocytes increases the formation of potent androgens to potentiate hyperandrogenism and induce FASN to promote lipid overload in PCOS adipocytes. We utilized differentiated human Simpson-Golabi-Behmel-Syndrome adipocytes as a model for PCOS adipocytes. First, we investigated the role of AKR1C3 in driving hyperandrogenism. Using discontinuous kinetic assays, we determined that the 11-oxygenated androgens were superior substrates for AKR1C3 compared to the classical androgens. Utilizing a high resolution mass spectrometric assay for the quantification of both classical and 11-oxygenated androgens, we determined that androgen conversion was dependent on AKR1C3. The 11-oxygenated androgens were inactivated by HSD11B1 identifying a novel role of this enzyme in regulating ligand occupancy of the androgen receptor. Second, we determined the role of AKR1C3 in regulating FASN. We determined that induction of both AKR1C3 and FASN are dependent on the same PI3K/AKT/mTOR/NRF2 signaling axis using both pharmacological and genetic manipulation. We found that FASN is induced by AKR1C3 independent of its enzymatic activity. We found that ARK1C3 interacts with and stabilizes the androgen receptor by preventing its ubiquitination and this leads to the induction of FASN in the absence of androgens. We found that inhibition of AKR1C3 and its interaction with AR prevents lipid droplet formation. We conclude that the both classical and 11-oxygenated androgens formed in adipocytes may contribute to the hyperandrogenic profile of PCOS women. We conclude that insulin induction of AKR1C3 regulates FASN, which promotes lipid overload in PCOS adipocytes in an androgen independent manner. This research identifies AKR1C3 as a potential therapeutic target to reduce hyperandrogenism and cardio-metabolic disease in PCOS women.

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Penning, Trevor, M
Date of degree
2023
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