Ranganathan S, Kern P A
Department of Medicine, Division of Endocrinology, University of Arkansas for Medical Sciences and the John L. McClellan Veterans Affairs Medical Center, Little Rock, Arkansas 72205, USA.
J Biol Chem. 1998 Oct 2;273(40):26117-22. doi: 10.1074/jbc.273.40.26117.
The thiazolidinediones troglitazone and BRL 49653 improve insulin sensitivity in humans and animals with insulin resistance. Adipose tissue lipoprotein lipase is an insulin-sensitive enzyme. We examined the effects of thiazolidinediones on lipoprotein lipase expression in adipocytes. When added to 3T3-F442A, 3T3-L1, and rat adipocytes in culture, troglitazone and BRL 49653 inhibited lipoprotein lipase activity. This inhibition was observed at concentrations as low as 0.1 microM and within 2 h after addition of the drug. Lipoprotein lipase activity was inhibited in differentiated adipocytes as well as the differentiating cells. Despite this decrease in enzyme activity, these drugs increased mRNA levels in undifferentiated 3T3-F442A and 3T3-L1 cells and had no effect on mRNA expression or synthesis of lipoprotein lipase in differentiated cells. Western blot analysis showed that these drugs did not affect the mass of the enzyme protein. Lipoprotein lipase activity in cultured Chinese hamster ovary cells was not inhibited by troglitazone. Glucose transport, biosynthesis of lipids from glucose or the biosynthesis of proteins were unaffected by thiazolidinediones in differentiated cells, whereas glucose transport and lipid biosynthesis were increased when these drugs were added during differentiation. These results show that troglitazone and BRL 49653 have a specific, post-translational inhibitory effect on lipoprotein lipase in adipocytes, yet they promote lipid accumulation and differentiation in preadipocytes.
噻唑烷二酮类药物曲格列酮和BRL 49653可改善人和动物的胰岛素抵抗，提高胰岛素敏感性。脂肪组织脂蛋白脂肪酶是一种胰岛素敏感酶。我们研究了噻唑烷二酮类药物对脂肪细胞中脂蛋白脂肪酶表达的影响。将曲格列酮和BRL 49653添加到培养的3T3-F442A、3T3-L1和大鼠脂肪细胞中时，它们会抑制脂蛋白脂肪酶的活性。在低至0.1微摩尔的浓度下以及添加药物后2小时内即可观察到这种抑制作用。在分化的脂肪细胞以及正在分化的细胞中，脂蛋白脂肪酶的活性均受到抑制。尽管酶活性有所下降，但这些药物却增加了未分化的3T3-F442A和3T3-L1细胞中的mRNA水平，并且对分化细胞中脂蛋白脂肪酶的mRNA表达或合成没有影响。蛋白质印迹分析表明，这些药物不会影响酶蛋白的量。曲格列酮不会抑制培养的中国仓鼠卵巢细胞中的脂蛋白脂肪酶活性。在分化细胞中，噻唑烷二酮类药物不会影响葡萄糖转运、葡萄糖脂质生物合成或蛋白质生物合成，而在分化过程中添加这些药物时，葡萄糖转运和脂质生物合成会增加。这些结果表明，曲格列酮和BRL 49653对脂肪细胞中的脂蛋白脂肪酶具有特异性的翻译后抑制作用，但它们会促进前脂肪细胞中的脂质积累和分化。
