Effect of sulfonylureas on triglyceride metabolism in the rat liver: possible role of the lysosomes in hepatic lipolysis.
Effect of sulfonylureas on triglyceride metabolism in the rat liver: possible role of the lysosomes in hepatic lipolysis.
复制标题
磺酰脲类药物对大鼠肝脏甘油三酯代谢的影响：溶酶体在肝脂肪分解中的可能作用。
DOI：
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发表时间：
1977
影响因子：
15.9
通讯作者：
P. Deschepper
中科院分区：
文献类型：
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作者：
L. Debeer;J. Thomas;G. Mannaerts;P. Deschepper
以前曾有人提出氯丙胺和其他降糖磺脲类药物干扰肝脏甘油三酯分解。由于内源性肝脏脂质储存的生酮是肝脏甘油三酯水解的一种测量方法，因此在禁食大鼠的分离肝细胞中测定了内源性脂质和外源性添加的油酸同位素的生酮，以试图确定磺脲类对肝脏脂质代谢的直接影响的性质。1 mM氯丙胺抑制内源性脂质生酮，而外源性油酸酯生酮无变化。在正常大鼠离体灌注肝中连续输注[3H]油酸，并在[3H]油酸培养的离体肝细胞中进一步研究氯丙酰胺对肝脏甘油三酯代谢的影响。在肝脏灌注实验中，1 mM氯丙酰胺增强了氚与甘油三酯（但不包括其他脂类）的结合，增加了肝脏甘油三酯含量和甘油三酯分泌。使用分离的细胞，0.5 mM氯丙胺可以证明类似的效果。氯丙酰胺、甲磺丁酰胺和甲磺丁酰胺均能抑制离体肝细胞内源性生酮，同时也能抑制大鼠肝脏均浆中溶酶体甘油三酯脂肪酶的活性。药物对碱性脂肪酶活性无抑制作用。去甲基糖二嗪（2-苯并磺胺-5-（β -羟基乙氧基）-嘧啶）在分离的肝细胞中不抑制内源性酮生成，也不影响溶酶体脂肪酶的活性。溶酶体药物氯喹在肝细胞中有明显的抗生酮作用。内源性酮生减少，肝脏甘油三酯积累增强，氯丙酰胺刺激肝脏甘油三酯输出归因于药物对肝脏甘油三酯分解的干扰。目前的结果也表明溶酶体在肝脂解中起重要作用。
It has been suggested previously that chlorpropamide and other hypoglycemic sulfonylureas interfere with hepatic triglyceride breakdown. Since ketogenesis from endogenous hepatic lipid stores is a measure of hepatic triglyceride hydrolysis, ketogenesis derived from endogenous lipids as well as ketogenesis derived from exogenously added isotopic oleate was determined in isolated hepatocytes from fasted rats in an attempt to identify the nature of the direct effects of sulfonylureas on hepatic lipid metabolism. Ketogenesis from endogenous lipids was inhibited by 1 mM chlorpropamide, while ketone production from exogenous oleate did not change. The effect of chlorpropamide on hepatic triglyceride metabolism was further studied in the isolated perfused liver of normal rats in the presence of a continuous [3H]oleate infusion and in isolated liver cells incubated in the presence of [3H]oleate. In liver perfusion experiments, 1 mM chlorpropamide enhanced the incorporation of tritium into triglycerides (but not other lipid classes) and increased both liver triglyceride content and triglyceride secretion. Using isolated cells similar effects could be demonstrated at 0.5 mM chlorpropamide. Chlorpropamide, tolbutamide, and carbutamide, all of which inhibited endogenous ketogenesis in isolated liver cells, also inhibited lysosomal triglyceride lipase activity in rat liver homogenates. The drugs were not inhibitory towards alkaline lipase activity. Demethylglycodiazin (2-benzolsulfonamid--5-(beta-hydroxyethoxy)-pyrimidin), which did not inhibit endogenous ketogenesis in isolated liver cells, did not affect lysosomal lipase activity. The lysosomotropic drug chloroquine was markedly antiketogenic when tested in liver cells. The reduction in endogenous ketogenesis, the enhanced accumulation of liver triglycerides, and the stimulation of hepatic triglyceride output by chlorpropamide are ascribed to an interference of the drug with hepatic triglyceride breakdown. The present results also suggest that the lysosomes play a significant role in hepatic lipolysis.