ATP Binding Cassette Transporter A1 (ABCA1) Associated Proteins:Potential Drug Targets in the Metabolic Syndrome and Atherosclerotic Disease?

Christa      Buechler; Sabrina      Bauer

Abstract

The metabolic syndrome is defined as a cluster of disorders including visceral obesity, insulin resistance, hypertension, hypertriglyceridemia and low HDL. Patients have an increased risk to develop atherosclerotic disease characterized by excessive macrophage cholesterol deposition in the vascular wall. HDL removes excess cellular cholesterol which is subsequently transported to the liver for biliary excretion and thereby preserves cholesterol homeostasis. Circulating HDL levels are maintained by hepatic ATP-binding cassette transporter A1 (ABCA1) which also transports peripheral cell cholesterol to extracellular lipid acceptors. Lipid export activity of ABCA1 improves pancreatic -cell function and ameliorates insulin release. ABCA1 affects plasma membrane cholesterol distribution and formation of lipid rafts representing signalling platforms for diverse receptors including toll-like receptor 4 (TLR4). Pharmacological activation of ABCA1 pathways presumably progresses metabolic diseases, and current approaches demonstrate beneficial effects of small peptides mimicking ABCA1 ligands which stabilize ABCA1 and enhance lipid efflux similar to its physiological acceptor apolipoprotein A-I. Research of the last decade has resulted in the identification of several ABCA1 binding proteins influencing ABCA1 signalling, stability and activity. In the current review the proteins suggested to form a complex with ABCA1 are summarized and their up to now characterized features towards ABCA1 functions are described.

Keywords: ATP binding cassette transporter, chronic overnutrition, apolipoprotein, metabolic syndrome, macrophage cholesterol, cholesterol homeostasis, physiological acceptor apolipoprotein A-I, cardiovascular diseases, Numerous epidemiological studies, apoA-I-lipid complexes by exocytosis, peripheral cells, systemic inflammation, circulating monocytes, less toxic, atherogenic lipoproteins