SUN-LB081 LXR Agonist 25-Hydroxycholesterol Modulates Plasma, Adrenal, and Hypothalamic Phosphoethanolamine Levels: Neuroendocrine Implications for HPA-Axis in Major Depressive Disorder

Plasma phosphoethanolamine (PEA) levels are significantly decreased in major depressive disorder (MDD) patients compared to healthy controls: Also, in chronic ACTH treatment mouse model of MDD, plasma and frontal cortex PEA were significantly decreased compared to vehicle treated controls: PEA has thus been proposed as a potential diagnostic biomarker for MDD. However, the neuroendocrine mechanism by which PEA changes in vivo, and its role in the pathobiology of MDD is not yet known. Previous in vitro studies reported that the endogenous LXR agonist 25-hydroxycholesterol, the intermediate precursor for the conversion of cholesterol to steroid hormones in the adrenal gland, caused increased PEA levels in cells. To understand PEA function in the neuroendocrine circuitry of MDD, in vivo effects of 25-hydroxylcholesterol on PEA levels in blood plasma, adrenal gland, and brain nuclei implicated in MDD were studied in mice. Both targeted and untargeted metabolomics analysis using capillary electrophoresis-mass spectrometry were applied to measure PEA and various metabolite levels in the respective tissues. Here we report that while acute LXR agonism with 25-hydroxycholesterol decreased plasma PEA levels, chronic LXR agonism significantly increased plasma PEA levels in both male and female mice. Moreover, in the adrenal gland where LXR agonism mediates the synthesis of glucocorticoids from cholesterol, 25-hydroxycholesterol significantly increased adrenal PEA levels in female mice; with no change in PEA in male mice compared to vehicle treated controls. Furthermore, in the hypothalamus compared to vehicle controls, LXR agonism caused significant PEA level decrease in female mice by 20%; and by 80% increase in male mice. Additionally, metabolomics results showed significant changes in levels of several metabolites in key brain and peripheral tissues of 25-hydroxycholesterol treated mice. These results are suggestive of a neuroendocrine role for PEA in the pathobiology of MDD; and that by way of LXR signaling PEA may impact the hypothalamic-pituitary-adrenal axis in the control of stress response. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.