Mechanisms of p42/44MAPK-induced LDL receptor expression

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Of all known risk factors promoting coronary artery disease, a high serum low density lipoprotein (LDL) level is the most important. The regulation of hepatic LDL receptor expression is a potential mechanism by which dietary and humoral factors alter plasma LDL levels, and upregulation of LDL receptor expression is the basis for current treatment of hypercholesterolemia. The negative regulation of LDL receptor transcription by sterols has been extensively delineated; however, the molecular mechanisms of induction and the signaling cascades controlling activity of critical nuclear factor(s) are not known. Recently, we provided the first evidence that specific activation of the p42/44mitogen-activated protein kinase (MAPK) is not only required but is sufficient to fully induce LDL receptor expression. Our recent observations supporting the requirement of CREB-binding protein (CBP) in p42/44MAPK-induced LDL receptor transcription are the basis of Specific Aim 1, and the studies proposed will link CBP acetyltransferase activity with modification of sterol responsive element binding proteins (SREBPs) and/or chromatin remodeling in the promoter region. Effects of CBP-SREBP protein-protein interactions on transactivation and on chromatin structures during the induction process will be examined by using a p42/44MAPK-responsive mammalian two-hybrid system and in vivo footprinting techniques. The Specific Aim 2 will study interleukin-1beta- and hepatocyte growth factor-induced LDL receptor expression to examine how p42/44MAPK participates during induction by sterol-sensitive and sterol-independent mechanisms. The Specific Aim 3 will establish a negative relationship between stress-activated p38MAPK alpha- isoform and LDL receptor expression and then examine the role of p38MAPK activation in stress-induced hypercholesterolemia through suppression of LDL receptor expression. This aim is based on our observation that specific inhibition of p38MAPK alpha-isoform induces LDL receptor expression via suppression of p42/44MAPK. Finally, in light of the crucial roles of MAPKs in hepatic cells, the Specific Aim 4 will examine the roles of p42/44MAPK and p38MAPK cascades in regulating expression of LDL and scavenger receptors that are a critical determinant of lipid accumulation in the macrophages and their conversion to foam cells. Defining the molecular mechanisms and the signaling pathways regulating the induction process will help in understanding the pathologic states under which the receptor pathways are perturbed, resulting in hypercholesterolemia. This knowledge could be exploited to develop improved hypercholesterolemia therapies and to reduce foam cell formation.