ApoA-I Facilitates ABCA1 Recycle/Accumulation to Cell Surface by Inhibiting Its Intracellular Degradation and Increases HDL Generation

Abstract

Objective— Calpain-mediated proteolysis is one of the major regulatory factors for activity of ATP-binding cassette transporter (ABC) A1. Helical apolipoproteins protect ABCA1 against this degradation and increase generation of HDL. We investigated the mechanism for this reaction focusing on roles of endocytotic internalization of ABCA1. Methods and Results— Surface ABCA1 was labeled with biotin and traced for its internalization and degradation. ABCA1 in the cell surface was internalized within 10 minutes regardless of the presence of apoA-I. ABCA1 was intracellularly degraded and was protected against this only when exposed to extracellular apoA-I before its endocytosis. Consequently, recycle of ABCA1 to the surface was enhanced, and surface ABCA1 was increased by apoA-I. Direct inhibition of ABCA1 endocytosis led to decrease of its degradation and increase of surface ABCA1. Generation of HDL increased in parallel with surface ABCA1. Conclusion— Surface ABCA1 is internalized and degraded, and apoA-I interferes with only the latter step to recycle ABCA1 to the surface. Increase of surface ABCA1 results in the increase of generation of HDL.