Diversity Supplement for “Post-translational regulation of LDLR”

ABSTRACT Elevated plasma LDL cholesterol is the main risk factor in cardiovascular disease (CVD), the leading cause of death in the United States. Cholesterol levels are regulated by complex feedback mechanisms that help maintain cellular and plasma cholesterol levels in check. While transcriptional mechanisms that control cholesterol homeostasis, such as SREBPs and LXRs are

well described, here we describe a novel post-transcriptional mechanism that is involved in controlling the mRNA stability of Ldlr mRNA. We have identified a family of RNA binding proteins (RBPs) that target specifically mRNAs and are important in cholesterol homeostasis. We show that hepatic loss of one or more of these RBPs in the liver results in increased levels of LDLR

mRNA and protein. In Specific Aim 1, we will identify the direct mRNA targets in vivo using CLIP- Seq and we will perform functional genomics to determine the effect of human variants in the LDLR 3’UTR. In Specific Aim 2, we will extend our preliminary data showing that loss of one of our RBPs in the liver profoundly protects from atherosclerosis. Using a ‘humanized’ lipoprotein

mouse atherosclerosis model, we have developed the hypothesis that loss of our RBP in the liver promotes uptake of LDL particles, thus protecting from atherosclerosis. Further, we hypothesize that the internalized cholesterol is then preferentially catabolized to bile acids. Thus, our mouse model will allow us to better understand how the liver channels cholesterol taken up from LDL

particles to ultimately protect from CVD.