Cardiovascular disease (CVD) is the leading cause of death in both men and women worldwide. Malfunction in lipoprotein metabolism and elevated levels of plasma cholesterol are known causes of CVD and about half of all Americans are likely to have at least one of these risk factors. Individual characteristics that present additional risk factors for CVD include, gender and other factors, which affect an individual?s internal hormonal milieu; age; diet; and genetic factors. Lipoprotein metabolism and cholesterol homeostasis are strongly regulated by low-density lipoprotein receptor (LDLR) and high- density lipoprotein receptor scavenger receptor type BI (SR-BI). Briefly, LDLR binds to plasma LDL and delivers LDL-cholesterol to peripheral tissues. In the liver, SR-BI, functions as a receptor for the cholesterol-rich HDL and serves to facilitate the selective delivery of HDL-cholesterol to the liver. Our preliminary studies demonstrate that SR-BI expression is induced, both in vitro and in vivo, by the ovarian hormone, 17?-estradiol (E2). We also show that the MLL-family of histone methylases coordinate with estrogen receptors (ER) to regulate E2-induced SR-BI expression. Moreover, knockdown of MLL2 decreases hepatic SR-BI expression and subsequently elevates plasma cholesterol level in male mice, while E2-treatment to ovariectomized (OVX) animals induces hepatic SR-BI expression. Here, we propose to further elucidate the detailed molecular/epigenetic mechanisms by which E2 regulates SR-B1 expression and resultant hepatic function in vitro and in vivo. Specifically we will study, roles of MLL2 and its histone methylation function in E2-induced SR-BI expression, using HepG2 cells overexpressing ER? or ER?, or in primary hepatocytes.
In aim 2, we will investigate the function of MLL2 in cholesterol uptake and efflux in vitro. We will also study the roles of MLL2 in SR-BI expression, and consequent hepatic function, in female mice in vivo. The proposed studies will reveal a novel epigenetic mechanism of E2-induced SR-BI gene expression and cholesterol homeostasis and our results will help in identifying novel target for the treatment of CVD. In addition to addressing an important scientific problem, this proposal will also serve to enrich student research experiences at UTA ? a minority serving institution. The experiments outlined will provide students with meaningful and high quality training opportunities. The end result will ultimately enhance the research training environment at UTA, and increase the prospects for our students to pursue future careers in health-related fields. 1
Steroid hormones play critical roles in controlling blood cholesterol level that is a key determinant of cardiovascular heath and disease. Herein experiments are proposed to understand the biochemical mechanism of estrogen signaling associated with cholesterol homeostasis. Completion of these studies will advance our understanding about mechanism of plasma cholesterol regulation, lipoprotein metabolism, and will open up new therapeutic avenues for the treatment of cardiovascular disease. 1
