Caveolin-1 facilitates internalization and degradation of ABCA1 and probucol oxidative products interfere with this reaction to increase HDL biogenesis.

Background And Aims: Expression of ATP binding cassette transporter (ABC) A1, a key membrane protein for biogenesis of high-density lipoprotein (HDL), is regulated not only by its gene transcription but also by its intracellular degradation to modulate plasma HDL concentration. We previously showed that inhibition of ABCA1 degradation by probucol oxidative products, spiroquinone (SQ) and diphenoquinone (DQ), increased HDL biogenesis and reverse cholesterol transport, and achieved reduction of atherosclerosis in animal models. The background mechanism has thus been investigated.

Methods: Involvement of caveolin-1, a protein of multiple functions in cell biology, particularly in cholesterol trafficking, has been examined for its roles in ABCA1 degradation as well as the effects of SQ and DQ on the reaction.

Results: ABCA1 protein was increased in caveolin-1-deficient mouse embryonic fibroblasts, not by increase of transcription but by decrease in its internalization and degradation. Transfection and expression of caveolin-1 normalized the protein level and the rate of degradation of ABCA1. Immunoprecipitation experiments demonstrated association between ABCA1 and caveolin-1 and SQ and DQ disrupted this interaction. The effects of SQ and DQ to increase ABCA1 and cell cholesterol release induced by apolipoprotein A-I were dependent on expression of caveolin-1. Fluorescence imaging of ABCA1 and caveolin-1 in cultured cells demonstrated their co-localization as well as its disruption by SQ and DQ, being consistent with the biochemical findings.

Conclusions: Caveolin-1 enhances internalization and degradation of ABCA1 by its association with ABCA1. Interference of this interaction by probucol oxidative products suppresses ABCA1 degradation and increase HDL biogenesis.