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, 17ß-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 ERa or ERß, 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.
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