Insulin-Induced AKR1C3 Induces Fatty Acid Synthase in a Model of Human PCOS Adipocytes

Abstract

Abstract Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women. In PCOS, insulin resistance and hyperandrogenism could drive the increased risk for cardiometabolic disease. Aldo-keto reductase family 1 member C3 (AKR1C3) is induced by insulin in PCOS adipocytes and is the predominant enzyme for potent androgen formation causing ligand-dependent androgen receptor (AR) activation. AR induces fatty acid synthase (FASN), a central enzyme for de novo lipogenesis. To investigate how insulin signaling induces AKR1C3 to promote lipid overload through induction of FASN, we used differentiated human Simpson–Golabi–Behmel syndrome adipocytes as a model for PCOS adipocytes. Induction of AKR1C3 and FASN was shown to be dependent on phosphoinositide 3-kinase/protein kinase B/ mammalian target of rapamycin/nuclear factor-erythroid 2-related factor 2 using pharmacological and genetic manipulation. FASN induction was shown to be AKR1C3 and AR dependent. Monofunctional AKR1C3 inhibitors, which competitively inhibit AKR1C3, did not block FASN induction, whereas bifunctional inhibitors, which competitively inhibit AKR1C3 and attenuate AR signaling by increasing AR degradation and ubiquitination, did suggesting a nonenzymatic role for AKR1C3 to stabilize AR. AKR1C3 and AR interacted as seen by co-immunoprecipitation, proximity ligation assay, and co-occupancy on FASN locus using chromatin immunoprecipitation–quantitative polymerase chain reaction assays in a ligand-dependent and ligand-independent manner. In the absence of androgens, bifunctional inhibitors prevented lipid droplet formation, whereas monofunctional inhibitors did not. We propose that AKR1C3 has 2 roles in PCOS: to catalyze potent androgen formation in adipocytes promoting hyperandrogenism and to induce FASN by stabilizing AR in the absence of androgens. AKR1C3 may be a therapeutic target for bifunctional inhibitors to reduce cardiometabolic disease in PCOS women.