Zinc Increases ABCA1 by Attenuating Its Clearance Through the Modulation of Calmodulin Activity

Aim: We previously revealed that Ca＋＋-activated calmodulin binds to ABCA1 by the region near the PEST sequence and retards its calpain-mediated degradation to increase HDL biogenesis. Calmodulin activity is reportedly modulated also by other nutritional divalent cations; thus, we attempted to determ...

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Bibliographic Details
Published in:Journal of Atherosclerosis and Thrombosis 2021/03/01, Vol.28(3), pp.261-270
Main Authors: Lu, Rui, Ishikawa, Takahiro, Tanaka, Mamoru, Tsuboi, Tomoe, Yokoyama, Shinji
Format: Article
Language:English
Subjects:
ATP binding cassette transporter A1
Calmodulin
Calpain
High density lipoprotein
Original
Zinc
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Summary:Aim: We previously revealed that Ca＋＋-activated calmodulin binds to ABCA1 by the region near the PEST sequence and retards its calpain-mediated degradation to increase HDL biogenesis. Calmodulin activity is reportedly modulated also by other nutritional divalent cations; thus, we attempted to determine whether Zn＋＋ is involved in the regulation of ABCA1 stability through the modulation of calmodulin activity. Methods: The effects of Zn＋＋ on ABCA1 expression was investigated in J774 mouse macrophage cell-line cells and HepG2 human hepatoma cell-line cells. Results: Zn＋＋ increased ABCA1 expression, not by increasing the mRNA but by attenuating its decay rate, more prominently in the presence of cAMP. Accordingly, it enhanced cell cholesterol release with extracellular apolipoprotein A-I. Calmodulin binding to ABCA1 was increased by Zn＋＋ and Ca＋＋. Zn＋＋ suppressed calpain-mediated hydrolysis of the peptide of ABCA1 cytosolic loop, including the PEST sequence and the calmodulin-binding site, in a calmodulin- dependent fashion, in the presence of the minimum amount of Ca＋＋ to activate calpain, but not calmodulin. Calpain activity was not directly inhibited by Zn＋＋ at the concentration for enhancing calmodulin binding to ABCA1. Conclusion: Nutritional divalent cation Zn＋＋ is involved in the regulation of ABCA1 activity and biogenesis of HDL through the modulation of calmodulin activity. The results were consistent with previous clinical findings that Zn＋＋ increased plasma HDL in the conditions of sympathetic activation, such as type 2 diabetes and chronic hemodialysis.
ISSN:1340-3478
1880-3873
DOI:10.5551/jat.55384