The biological function of sex and sex-steroid hormones in intestinal lipid and incretin metabolism

点击翻译按钮获取中文摘要

In my NSERC program(2013-2018) I have discovered that the intestine is an androgen-sensitive organ via the androgen receptor (AR), and androgens can modulate whole-body lipid metabolism. The intestine secretes incretins which have also been shown to modulate lipid metabolism. In this emerging field we have limited understanding of how sex as a biological variable and sex-steroid hormones modulate intestinal biology.   My new data shows testosterone (T) via the AR increases fatty acid and cholesterol absorption into intestinal lymph. I have also shown dietary lipid reduces plasma testosterone levels. The intestine can metabolize sex-steroids, and dietary lipids and incretins may impact these pathways. My preliminary data forms the rationale of my new discovery program. My overall working hypothesis is that sex-steroids are regulators of intestinal lipid absorption and incretin secretion, and dietary lipids impact intestinal sex-steroid metabolism. The following objectives will be addressed using multi-model and integrative biological approaches; Primary Objective I (short-term): To determine the effect of sex and sex-steroids on intestinal incretin secretion and lipid absorption. I will use gonadectomized and sex-steroid treated male and female rodent models to determine the effect of sex vs sex-steroids on intestinal incretin secretion and lipid absorption using intestinal-lymphatic cannulation methods. Gene silencing and promoting RNA for AR and ER will be used to determine the direct role of these receptors in these pathways. The expected outcome will be to confirm sex-steroids, androgens and estrogens, upregulate lipid absorption and incretin secretion directly via the AR and ER. Primary Objective II (mid-term): To determine the molecular mechanisms of how sex-steroids regulate intestinal incretin and lipogenic molecular signalling pathways. I will use intestinal tissue and primary enterocytes to measure gene and protein expression of AR, ER and lipogenic nuclear receptors, incretins and lipid synthesis proteins and transporters. The expected outcome will be that the AR and ER regulate nuclear transcription factors and the activity of proteins involved in these pathways. Primary Objective III (long-term): To determine the effect of dietary lipids on sex-steroid hormones, and the relationship to intestinal steroidogenesis, incretin and lipid metabolism. I will test the effect of diets high and low in fat on lymph and plasma lipids, incretins and sex-steroids. The primary expected outcome will be that diets high in fat reduce plasma sex-steroid levels by modulating steroidogenesis in the intestine. Significance and Impact: This research aims to explain differences between the male and female sex in lipid metabolism and intestinal physiology, and will translate to understanding how sex-steroids regulate intestinal function and adaptation which can be applied in biomedical and agricultural sectors.