Denton R M, Brownsey R W
Philos Trans R Soc Lond B Biol Sci. 1983 Jul 5;302(1108):33-45. doi: 10.1098/rstb.1983.0036.
Insulin stimulates fatty acid synthesis in white and brown fat cells as well as in liver and mammary tissue. Hormones that increase cellular cyclic AMP concentrations inhibit fatty acid synthesis, at least in white adipose tissue and liver. These changes in fatty acid synthesis occur within minutes. In white fat cells, they are brought about not only by changes in glucose transport but also changes in the activities of pyruvate kinase, pyruvate dehydrogenase and acetyl-CoA carboxylase. The basis of the alterations in pyruvate kinase activity in fat cells is not understood. Unlike the liver isoenzyme, the isoenzyme present in fat cells does not appear to be phosphorylated either in the absence or presence of hormones. The changes in pyruvate dehydrogenase activity in fat cells are undoubtedly due to changes in phosphorylation of the alpha subunits. Insulin appears to act by causing the parallel dephosphorylation of all three sites. The persistence of the effect of insulin during the preparation and subsequent incubation of mitochondria has allowed the demonstration that insulin acts mainly by stimulating pyruvate dehydrogenase phosphatase rather than inhibiting the kinase. Acetyl-CoA carboxylase within fat cells is phosphorylated on a number of different sites. The exposure of cells to insulin leads to activation of the enzyme and this is associated with increased phosphorylation of a specific site on the enzyme. Exposure to adrenalin, which results in a marked diminution in activity, also causes a small increase in the overall level of phosphorylation, but this increase is due to an enhanced phosphorylation of different sites; probably those phosphorylated by cyclic-AMP-dependent protein kinase. Acetyl-CoA carboxylase is one of a number of proteins in fat cells that exhibit increased phosphorylation with insulin. Others include ATP-citrate lyase, the ribosomal protein S6, the beta subunit of the insulin receptor and a heat and acid stable protein of Mr 22000. Changes in phosphorylation of ATP-citrate lyase do not appear to result in any appreciable changes in catalytic activity. A central aspect of insulin action may be the activation and perhaps release of a membrane-associated protein kinase. Plasma membranes from fat cells have been shown to contain a cyclic-nucleotide-independent kinase able to phosphorylate and activate acetyl-CoA carboxylase. Furthermore, high-speed supernatant fractions from cells previously exposed to insulin contain elevated levels of the same or similar kinase activity capable of phosphorylating both ATP-citrate lyase and acetyl-CoA carboxylase.
胰岛素可刺激白色和棕色脂肪细胞以及肝脏和乳腺组织中的脂肪酸合成。至少在白色脂肪组织和肝脏中，能提高细胞环磷酸腺苷（cAMP）浓度的激素会抑制脂肪酸合成。脂肪酸合成的这些变化在数分钟内即可发生。在白色脂肪细胞中，这些变化不仅由葡萄糖转运的改变引起，还由丙酮酸激酶、丙酮酸脱氢酶和乙酰辅酶A羧化酶的活性变化所致。脂肪细胞中丙酮酸激酶活性改变的基础尚不清楚。与肝脏中的同工酶不同，脂肪细胞中存在的同工酶在有无激素的情况下似乎都不会被磷酸化。脂肪细胞中丙酮酸脱氢酶活性的变化无疑是由于α亚基磷酸化的改变。胰岛素似乎通过使所有三个位点同时去磷酸化而起作用。在制备线粒体并随后进行孵育的过程中，胰岛素的作用持续存在，这使得人们能够证明胰岛素主要通过刺激丙酮酸脱氢酶磷酸酶而非抑制激酶来发挥作用。脂肪细胞内的乙酰辅酶A羧化酶在多个不同位点被磷酸化。细胞暴露于胰岛素会导致该酶活化，这与该酶特定位点磷酸化增加有关。暴露于肾上腺素会导致活性显著降低，同时也会使磷酸化的总体水平略有增加，但这种增加是由于不同位点磷酸化增强所致；可能是那些被环磷酸腺苷依赖性蛋白激酶磷酸化的位点。乙酰辅酶A羧化酶是脂肪细胞中多种随着胰岛素作用而磷酸化增加的蛋白质之一。其他蛋白质包括ATP - 柠檬酸裂解酶、核糖体蛋白S6、胰岛素受体的β亚基以及一种分子量为22000的热稳定和酸稳定蛋白。ATP - 柠檬酸裂解酶磷酸化的变化似乎不会导致催化活性有任何明显变化。胰岛素作用的一个核心方面可能是一种膜相关蛋白激酶的激活，或许还有释放。已证明脂肪细胞的质膜含有一种不依赖环核苷酸的激酶，该激酶能够磷酸化并激活乙酰辅酶A羧化酶。此外，先前暴露于胰岛素的细胞的高速上清液部分含有升高水平的相同或相似激酶活性，该活性能够磷酸化ATP - 柠檬酸裂解酶和乙酰辅酶A羧化酶。
