Shimomura I, Shimano H, Korn B S, Bashmakov Y, Horton J D
Department of Molecular Genetics, University of Texas, Southwestern Medical Center, Dallas, Texas 75235, USA.
J Biol Chem. 1998 Dec 25;273(52):35299-306. doi: 10.1074/jbc.273.52.35299.
Previous studies have shown that the rate of fatty acid synthesis is elevated by more than 20-fold in livers of transgenic mice that express truncated nuclear forms of sterol regulatory element-binding proteins (SREBPs). This was explained in part by an increase in the levels of mRNA for the two major enzymes of fatty acid synthesis, acetyl-CoA carboxylase and fatty acid synthase, whose transcription is stimulated by SREBPs. Fatty acid synthesis also requires a source of acetyl-CoA and NADPH. In the current studies we show that the levels of mRNA for ATP citrate lyase, the enzyme that produces acetyl-CoA, are also elevated in the transgenic livers. In addition, we found marked elevations in the mRNAs for malic enzyme, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase, all of which produce NADPH. Finally, we found that overexpressing two of the SREBPs (1a and 2) led to elevated mRNAs for stearoyl-CoA desaturase 1 (SCD1), an isoform that is detectable in nontransgenic livers, and SCD2, an isoform that is not detected in nontransgenic livers. This stimulation led to an increase in total SCD activity in liver microsomes. Together, all of these changes would be expected to lead to a marked increase in the concentration of monounsaturated fatty acids in the transgenic livers, and this was confirmed chromatographically. We conclude that expression of nuclear SREBPs is capable of activating the entire coordinated program of unsaturated fatty acid biosynthesis in mouse liver.
先前的研究表明，在表达截短形式核固醇调节元件结合蛋白（SREBPs）的转基因小鼠肝脏中，脂肪酸合成速率提高了20多倍。部分原因是脂肪酸合成的两种主要酶，即乙酰辅酶A羧化酶和脂肪酸合酶的mRNA水平增加，其转录受到SREBPs的刺激。脂肪酸合成还需要乙酰辅酶A和NADPH来源。在当前研究中，我们表明，产生乙酰辅酶A的酶——ATP柠檬酸裂解酶的mRNA水平在转基因肝脏中也升高。此外，我们发现苹果酸酶、葡萄糖-6-磷酸脱氢酶和6-磷酸葡萄糖酸脱氢酶的mRNA显著升高，所有这些酶都产生NADPH。最后，我们发现过表达两种SREBPs（1a和2）导致硬脂酰辅酶A去饱和酶1（SCD1，一种在非转基因肝脏中可检测到的异构体）和SCD2（一种在非转基因肝脏中未检测到的异构体）的mRNA升高。这种刺激导致肝脏微粒体中总SCD活性增加。总之，所有这些变化预计会导致转基因肝脏中单不饱和脂肪酸浓度显著增加，这一点通过色谱分析得到了证实。我们得出结论，核SREBPs的表达能够激活小鼠肝脏中不饱和脂肪酸生物合成的整个协调程序。
