3:00 pm - 4:00 pm
A graduate exam seminar is a presentation of the student’s final research project for their degree.
This is an ALES MSc course-based seminar by Thy Ton. This seminar is open to the general public to attend.
Meeting ID: 978 0653 6406 Passcode: 726180
Project Topic: Androgens Effects on Lipid and Insulin-Glucose Metabolism in Control and Polycystic Ovary Syndrome
MSc with Dr. Donna Vine
Introduction: Polycystic ovary syndrome (PCOS) is a common metabolic-endocrine disorder characterized by menstrual irregularities, biochemical or clinical evidence of hyperandrogenism (high testosterone) and enlarged polycystic ovaries in women of reproductive age. PCOS is highly associated with insulin resistance and dyslipidemia. Women with PCOS have a 2-fold higher risk of developing cardiovascular disease (CVD). Atherogenic dyslipidemia, including fasting and non-fasting lipemia, occurs in 70% of PCOS and is positively correlated with plasma androgens. We have shown women with PCOS have increased fasting and non-fasting plasma TG and chylomicron-apolipoprotein(apo)B48. We have also shown in a PCOS-prone rodent model that flutamide (androgen receptor inhibitor) decreases plasma triglycerides (TG), and intestinal triglyceride (TG) and chylomicron-apoB48 secretion. However, the direct effect of androgens on intestinal lipid absorption and metabolism remains unclear. The significance is androgens may adversely regulate lipid absorption and secretion in contributing to atherogenic dyslipidemia in PCOS.
Aims: The aim of this study was to determine the effect of androgens (testosterone: T and dihydrotestosterone: DHT) on intestinal lipid absorption and secretion pathways in a control and PCOS-prone rodent model.
Methods: PCOS-prone and control rodents were treated with androgens (T and DHT: 1000 ug/kg/day) for 7 days, and then the intestinal lymph duct was cannulated to determine lipid (cholesterol and TG) and chylomicron-apoB48 secretion in the fasted and fed stated, following saline and intralipid infusion into the duodenum, respectively. Radiolabeled lipids (3H-cholesterol, 14C-16:0) were used to assess lipid absorption.
Results: In the PCOS-prone group, the concentration of fasting plasma TG was higher compared to the control group, 1074 171.7 mg/dl vs 40.83 6.58 mg/dl, p<0.0001. The total cholesterol concentration was elevated by 36% in the PCOS-prone compared to the control group (p<0.005). The PCOS-prone group had 43.46% and 31.19% higher fasting plasma apoB48 and apoB100 compared to the control group (p<.0001). There was no significant difference in intestinal secretion of TG and cholesterol between PCOS-prone and control groups in the fasted and fed states. In the control group T and DHT did not alter intestinal lymph secretion of TG, cholesterol or apoB48. However, T and DHT treatment lowered TG (14C-16:0, control 40.58 ± 2.26%; T: 13.28 ± 8.45 %; DHT: 17.20 ± 2.45 %, p<0.05) and cholesterol absorption (3H-cholesterol, control: 28.33 ± 2.03 %; T: 6.43 ± 4.26 %; DHT: 9.75 ± 1.38%, p<0.05) in the control group. In contrast, T (46.65 ± 20.66 mg/ml) and DHT (34.83 ± 21.12 mg/ml) treatment increased TG secretion > 3 fold in the PCOS-prone group (12.48 ± 6.34 mg/ml) in the fed state (p<0.0001). DHT but not T treatment significantly increased absorption of TG (14C-16:0) in the PCOS-prone group by >55% (p<0.05). In both the fasting and fed state, T increased (57-78%) and DHT decreased (52-85%) apoB48 secretion in the PCOS-prone group (p<0.05). The expression of intestinal steroidogenic AR mRNA was 53.55% lower in PCOS-prone group compared to the control group (p<0.05). There was higher mRNA expression of LDLR, SREBP1, LXRα and HMGCoA in the PCOS-prone compared to the control group. Following T and DHT treatment, there were no differences in expression of these genes in the control or PCOS-prone groups. Microsomal triglyceride transfer protein (MTP) mRNA expression of lipoprotein assembly, was increased by >30% in the PCOS-prone group treated with testosterone.
Conclusion: T and DHT treatment differentially modulate chylomicron-apoB48, cholesterol and TG secretion and absorption in control and PCOS-prone conditions. In PCOS, TG absorption is increased in response to androgen treatment, and this is consistent with our clinical findings of hypertriglyceridemia in women with PCOS. Understanding the mechanisms of androgen induced dyslipidemia is important in developing interventions to target atherogenic dyslipidemia and CVD risk in PCOS.