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.
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 J774mouse macrophage cell-line cells and HepG2humanhepatoma 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.
Entities:
Keywords:
ATP binding cassette transporter A1; Calmodulin; Calpain; High density lipoprotein; Zinc
Authors: M Porsch-Ozcurumez; T Langmann; S Heimerl; H Borsukova; W E Kaminski; W Drobnik; C Honer; C Schumacher; G Schmitz Journal: J Biol Chem Date: 2001-01-22 Impact factor: 5.157
Authors: Gudrun Reiterer; Ruth MacDonald; Jim D Browning; Jason Morrow; Sergey V Matveev; Alan Daugherty; Eric Smart; Michal Toborek; Bernhard Hennig Journal: J Nutr Date: 2005-09 Impact factor: 4.798