Role of the adaptor protein PDZK1 in controlling the HDL receptor SR-BI

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Abstract
Regulation of lipoprotein receptor activity influences lipoprotein metabolism, related physiology and pathophysiology. Adaptor proteins that bind to the LDL or HDL receptors apparently link these receptors to cellular components essential for their normal functioning. Here, we focus on the influence of PDZK1 on the HDL receptor scavenger receptor class B type I (SR-BI), with emphasis on the roles played by its individual PDZ domains, the impact in regulating HDL metabolism and the relevance for cardiovascular disease. PDZK1 plays an essential role in maintaining hepatic SR-BI levels and controlling HDL metabolism, protects against the development of atherosclerosis in a murine model and also mediates SR-BI-dependent regulation of endothelial cell biology by HDL, suggesting that PDZK1 plays multiple roles in normal physiology and may influence associated disorder. All four PDZ domains of PDZK1 appear necessary to promote normal hepatic expression, function and intracellular localization of SR-BI. SR-BI mediates several features of HDL metabolism and function, some of which depend on SR-BI's interaction with PDZK1. Exploration of the structure and function of PDZK1 and the mechanisms by which it controls SR-BI will provide additional insights into HDL metabolism and may provide the basis for new therapeutic modalities for cardiovascular disease.