NK-104, a potent new 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, enhances posttranslational catabolism of apolipoprotein B-100 and inhibits secretion of apolipoprotein B-100 and triacylglycerols from HepG2 cells

The effects of NK-104, a new, potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on the secretion and intracellular catabolism of apoli poprotein B-100 (apo) and on lipid metabolism in HepG2 cells were investiga ted. The cells were treated with NK-104 1 or 10 mu M for 3 or 24 hours in 1 % bovine serum albumin-containing medium. To examine intracellular apo B ca tabolism, the cells were labeled with S-35-methionine for 10 minutes and fo llowed for up to 90 minutes. NK-104 reduced the secretion of apo B and S-35 -labeled apo B, The degradation rate of intracellular S-35-labeled apo B wa s faster in cells treated with NK-104 than in controls, suggesting that apo B stability was decreased by treatment with NK-104, NK-104 reduced signifi cantly the intracellular levels and synthesis of cholesterol and cholestery l ester in HepG2 cells. The agent reduced the secretion of labeled triacylg lycerols without affecting intracellular triacylglycerol synthesis. Results of this study suggest that NK-104 reduced the secretion of apo B by enhanc ing degradation of the protein, This effect may be mediated through changes in the intracellular metabolism of cholesterol or cholesteryl ester.