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 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.