SUN-019 Androgens Modulate Lipid Metabolism and Absorption in Control and Polycystic Ovary-Metabolic Syndrome Conditions

Abstract

Introduction: In polycystic ovary syndrome (PCOS) a high plasma level of androgens has been correlated with an adverse plasma lipid profile. At present we do not know the physiological or mechanistic pathways of how androgens regulate lipid metabolism under control or PCOS conditions. We have shown flutamide, an androgen receptor (AR) inhibitor, reduces the plasma concentration of triglycerides (TG) and apoB-lipoproteins, and intestinal secretion of TG. Aim: The aim of this study was to determine the direct physiological and mechanistic effects of androgens, Testosterone (T) and dihydrotestosterone (DHT), on lipid metabolism using a PCOS-prone rodent model. Methods: Control and PCOS-prone animals were administered vehicle, T or DHT for 7 days. PCOS-prone animals also present with the Metabolic Syndrome (MetS). Following treatment animals underwent a mesenteric lymphatic cannulation procedure to determine effects on intestinal chylomicron (CM-apoB48) and lipid secretion, and absorption using radiolabelled [³H]-cholesterol and [14C]-palmitic acid. Results: Plasma LDL-C was increased with DHT treatment in control animals, and with both T & DHT treatment in PCOS. Intestinal absorption of TG and cholesterol were increased in T and DHT treated PCOS animals but not control animals. Whereas DHT reduced intestinal CM-apoB48 secretion in both control and PCOS groups. These effects were associated with changes in genes and protein expression in lipogenic (SREBP1a/c&2, SREBP1c, SREBP-2, ACC) and steroidogenic pathways (AR, ER and SRDA51) in the liver and intestine. Conclusion: These results demonstrate androgens modulate lipid metabolism and absorption. T and DHT differentially affect intestinal chylomicron secretion and lipid absorption in PCOS-MetS and control conditions. In conclusion, these results suggest that androgens may directly cause or exacerbate lipid and lipoprotein metabolism in conditions of hyperandrogenemia and the MetS.