Lanford R E, Estlack L, White A L
Department of Virology and Immunology, Southwest Foundation for Biomedical Research, San Antonio, TX 78245-0549, USA.
J Lipid Res. 1996 Oct;37(10):2055-64.
Neomycin therapy reduces plasma levels of low density lipoprotein and lipoprotein[a] (Lp[a]). To determine whether neomycin directly alters the biogenesis of Lp[a], we have examined the effect of neomycin on apolipoprotein[a] (apo[a]) synthesis and secretion in primary cultures of baboon hepatocytes. Using this system, we have previously shown that apo[a] is synthesized as a lower molecular weight precursor that upon maturation becomes associated with the cell surface before release into the culture medium. Treatment of hepatocytes with 10 mM neomycin reduced levels of apo[a] in the culture medium by as much as 12-fold. Although a portion of the reduced secretion could be accounted for by a reduction in total protein synthesis, the greatest effect of neomycin on apo[a] secretion was to decrease the release of mature apo[a] from the hepatocyte cell surface into the culture medium. Treatment of hepatocyte cultures with trypsin confirmed that mature apo[a] in neomycin-treated cells was still transported to the cell surface. Examination of related antibiotics demonstrated that inhibition of apo[a] secretion is a general property shared by the deoxystreptamine antibiotics. The mechanism by which neomycin affects the apo[a]-cell surface interaction is not known, but neomycin is known to perturb cell surface membranes, inhibit the interaction of some ligands with their cell surface receptors, and inhibit the metabolism of phosphatidylinositol 4,5 biphosphate. These studies suggest that cell surface association of apo[a] may play a role in Lp[a] biogenesis in vivo.
新霉素疗法可降低血浆中低密度脂蛋白和脂蛋白[a]（Lp[a]）的水平。为了确定新霉素是否直接改变Lp[a]的生物合成，我们研究了新霉素对狒狒肝细胞原代培养物中载脂蛋白[a]（apo[a]）合成和分泌的影响。利用该系统，我们先前已表明apo[a]是以较低分子量的前体形式合成的，该前体成熟后在释放到培养基中之前会与细胞表面结合。用10 mM新霉素处理肝细胞可使培养基中apo[a]的水平降低多达12倍。尽管分泌减少的一部分可归因于总蛋白合成的减少，但新霉素对apo[a]分泌的最大影响是减少成熟apo[a]从肝细胞表面释放到培养基中。用胰蛋白酶处理肝细胞培养物证实，新霉素处理的细胞中的成熟apo[a]仍被转运到细胞表面。对相关抗生素的研究表明，抑制apo[a]分泌是脱氧链霉胺类抗生素共有的特性。新霉素影响apo[a]与细胞表面相互作用的机制尚不清楚，但已知新霉素会扰乱细胞表面膜、抑制某些配体与其细胞表面受体的相互作用，并抑制磷脂酰肌醇4,5-二磷酸的代谢。这些研究表明，apo[a]与细胞表面的结合可能在体内Lp[a]的生物合成中起作用。
