The Possible Role of Ca^<2+> on the Activation of Microsomal Triglyceride Transfer Protein in Rat Hepatocytes(Pharmacology)

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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 Ca^<2+> on MTP activity in hepatocytes. Exogenous CaCl_2 and calmodulin increased MTP activity dose-dependently, and calcium ionophore A23187 (A23187) also increased total Ca^<2+> level and MTP activity in hepatocytes. Moreover, MTP activity increased by CaCl_2 or A23187 was abrogated in the presence of EDTA, a Ca^<2+> 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 Ca^<2+> 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 Ca^<2+> contributes directly or indirectly to MTP activation. In conclusion, the inhibition of MTP activity via the suppression of hepatocellular Ca^<2+> may result in the inhibition of hypertriglyceridemia.
公益社団法人日本薬学会の論文
2005-08-01