The Possible Role of Ca²⁺ on the Activation of Microsomal Triglyceride Transfer Protein in Rat Hepatocytes

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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 CaCl₂ or A23187 was abrogated in the presence of EDTA, a Ca²⁺ chelator. MTP activity was increased by the simultaneous addition of CaCl₂ 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.