The possible role of Ca2+ on the activation of microsomal triglyceride transfer protein in rat hepatocytes

Abstract

Microsomal triglyceride (TG) transfer protein (MTP) is involved in the secretion of TG-rich very low-density lipoprotein (VLDL), a process which leads to the generation of hypertriglyceridemia and atherosclerosis. We investigated the possible role of Ca2+ on MTP activity in hepatocytes. Exogenous CaCl2 and calmodulin increased MTP activity dose-dependently, and calcium ionophore A23187 (A23187) also increased total Ca2+ level and MTP activity in hepatocytes. Moreover, MTP activity increased by CaCl 2 or A23187 was abrogated in the presence of EDTA, a Ca2+ chelator. MTP activity was increased by the simultaneous addition of CaCl 2 and calmodulin. However, this increase was inhibited by N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W-7), a Ca2+ antagonist. A23187 increased the release of TG and cholesterol from hepatocytes, and these were inhibited by EDTA. A23187 also increased the ratio of TG to HDL-cholesterol in hepatocytes culture medium, which indicates the release of TG is higher than that of HDL-cholesterol from hepatocytes. Thus, our findings demonstrate that hepatocellular Ca2+ contributes directly or indirectly to MTP activation. In conclusion, the inhibition of MTP activity via the suppression of hepatocellular Ca2+ may result in the inhibition of hypertriglyceridemia. © 2005 Pharmaceutical Society of Japan.