Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes
Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes
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DOI：
10.1074/jbc.274.50.35832
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发表时间：
1999-12-10
影响因子：
4.8
通讯作者：
Yamada, N
中科院分区：
文献类型：
--
作者：
Shimano, H;Yahagi, N;Yamada, N
为了阐明固醇调节元件结合蛋白-1（SREBP-1）的生理作用，在禁食-再喂养处理后，估计SREBP-1基因敲除小鼠中编码各种脂肪生成酶的基因的肝脏mRNA水平，所述禁食-再喂养处理是诱导脂肪生成酶的既定饮食操作。在禁食状态下，野生型和SREBP-1（-/-）小鼠中所有脂肪生成酶的mRNA水平始终较低。然而，SREBP-1的缺乏严重损害了脂肪酸合成基因（如乙酰辅酶A羧化酶、脂肪酸合成酶和硬脂酰辅酶A去饱和酶）的肝脏mRNA的显著诱导，这在野生型小鼠中重新喂养时观察到。此外，在SREBP-1（-/-）小鼠中，其他脂肪生成酶（甘油-3-磷酸酰基转移酶、ATP柠檬酸裂解酶、苹果酸酶、葡萄糖-6-磷酸脱氢酶和S14 mRNA）的再喂养反应完全消失。与此相反，胆固醇生物合成基因的mRNA水平升高，在refed SREBP-1（-/-）的肝脏伴随着核SREBP-8蛋白的增加。当喂食高碳水化合物饮食14天时，SREBP-1（-/-）小鼠中这些脂肪生成酶的mRNA水平也显著低于野生型小鼠。这些数据表明，SREBP-1在肝脏中脂肪生成的诱导中起关键作用，但在碳水化合物消耗过量能量时，在肝脏中胆固醇生物合成的诱导中不起关键作用。
To elucidate the physiological role of sterol regulatory element-binding protein-1 (SREBP-1), the hepatic mRNA levels of genes encoding various lipogenic enzymes were estimated in SREBP-1 gene knockout mice after a fasting-refeeding treatment, which is an established dietary manipulation for the induction of lipogenic enzymes. In the fasted state, the mRNA levels of all lipogenic enzymes were consistently low in both wildtype and SREBP-1(-/-) mice. However, the absence of SREBP-1 severely impaired the marked induction of hepatic mRNAs of fatty acid synthetic genes, such as acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase, that was observed upon refeeding in the wild-type mice. Furthermore, the refeeding responses of other lipogenic enzymes, glycerol-3-phosphate acyltransferase, ATP citrate lyase, malic enzyme, glucose-6-phosphate dehydrogenase, and S14 mRNAs, were completely abolished in SREBP-1(-/-) mice. In contrast, mRNA levels for cholesterol biosynthetic genes were elevated in the refed SREBP-1(-/-) livers accompanied by an increase in nuclear SREBP-8 protein. When fed a high carbohydrate diet for 14 days, the mRNA levels for these lipogenic enzymes were also strikingly lower in SREBP-1(-/-) mice than those in wild-type mice. These data demonstrate that SREBP-1 plays a crucial role in the induction of lipogenesis but not cholesterol biosynthesis in liver when excess energy by carbohydrates is consumed.