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 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 apolipo-protein 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.