Signal Transduction Pathways Provide Opportunities to Enhance HDL and apoAI-Dependent Reverse Cholesterol Transport

Vishwaroop      Mulay; Peta      Wood; Carles      Rentero; Carlos      Enrich; Thomas      Grewal

Abstract

Binding of High Density Lipoprotein (HDL) and its major apolipoprotein A-I (apoA-I) to cell surface receptors is believed to initiate a plethora of signaling cascades that promote atheroprotective cell behavior, including the removal of excess cholesterol from lipid-loaded macrophages. More specifically, HDL and apoA-I binding to scavenger receptor BI (SR-BI) and ATP-binding cassette (ABC) transporter A1 has been shown to activate protein kinase A and C (PKA, PKC), Rac/Rho GTPases, Janus Kinase 2 (JAK2), calmodulin as well as mitogen-activated protein kinases (MAPK). Some of these signaling events upregulate mobilization of cholesterol from cellular pools, while others promote efflux pathways through increased expression, stability, and cell surface localization of SR-BI and ABCA1. This review aims to summarize the current knowledge of HDL- and apoA-I -induced signal transduction pathways that are linked to cholesterol efflux and discusses the underlying mechanisms that could couple ligand binding to SR-BI and ABCA1 with signaling and cholesterol export. Additional focus is given on the potential of pharmacological intervention to modulate the activity of signaling cascades for the inhibition or regression of cholesterol accumulation in atherosclerotic lesions.

Keywords: ABCA1, cholesterol efflux, HDL, MAPK, PKA, PKC, signal transduction, SR-BI, Janus Kinase 2 (JAK2), Cholesteryl esters, lysosomal compartments, lipoproteins, stimulates multiple signaling pathways, cardiovascular disease, plasma membrane microdomains