MEDICA 16 inhibits hepatic acetyl-CoA carboxylase and reduces plasma triacylglycerol levels in insulin-resistant JCR:LA-cp rats
MEDICA 16 inhibits hepatic acetyl-CoA carboxylase and reduces plasma triacylglycerol levels in insulin-resistant JCR:LA-cp rats
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DOI：
10.2337/diabetes.51.5.1548
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发表时间：
2002-05-01
期刊：
影响因子：
7.7
通讯作者：
Lopaschuk, GD
中科院分区：
文献类型：
--
作者：
Atkinson, LL;Kelly, SE;Lopaschuk, GD
肝脏和骨骼肌细胞内三酰甘油（TG）含量与胰岛素抵抗有关，且TG含量与胰岛素抵抗的发生存在显著相关性。由于乙酰辅酶A羧化酶（ACC）是肝脏脂肪酸生物合成的限速酶和肌肉脂肪酸氧化的关键调节剂，我们研究了ACC是否在细胞内TG的积累中发挥作用。我们还确定了5 '-AMP活化蛋白激酶（AMPK）在这一过程中的潜在作用，因为它可以磷酸化和抑制肝脏和肌肉中的ACC活性。在胰岛素抵抗形成的时间范围内，检查胰岛素抵抗JCR：LA-cp大鼠肝脏和骨骼肌中的TG含量、ACC和AMPK。12周龄时，肝脏TG含量升高了三倍，骨骼肌TG含量升高了七倍。与瘦龄匹配的对照组相比，12周龄JCR：LA-cp大鼠的肝脏ACC活性显著升高（8.75 +/- 0.53 vs. 3.30 +/- 0.18 nmol . min（-1）。mg（-1）），尽管AMPK活性也增加。观察到的肝ACC活性增加伴随着ACC蛋白表达增加300%。在12周的JCR：LA-cp大鼠的骨骼肌中，ACC活性、ACC蛋白表达或AMPK活性没有显著差异。用MEDICA 16（一种ATP-柠檬酸裂解酶抑制剂）治疗12周的JCR：LA-cp大鼠导致肝脏ACC和AMPK活性降低，但对骨骼肌ACC和AMPK无影响。我们的数据表明，肌肉中ACC或AMPK活性的改变并不有助于胰岛素抵抗的发展。然而，在JCR：LA-cp大鼠肝脏ACC活性增加似乎有助于脂质异常的发展，虽然这种增加似乎不会发生继发于AMPK活性降低。
Intracellular triacylglycerol (TG) content of liver and skeletal muscle contributes to insulin resistance, and a significant correlation exists between TG content and the development of insulin resistance. Because acetylCoA carboxylase (ACC) is the rate-limiting enzyme for liver fatty acid biosynthesis and a key regulator of muscle fatty acid oxidation, we examined whether ACC plays a role in the accumulation of intracellular TG. We also determined the potential role of 5'-AMP-activated protein kinase (AMPK) in this process, since it can phosphorylate and inhibit ACC activity in both liver and muscle. TG content, ACC, and AMPK were examined in the liver and skeletal muscle of insulin-resistant JCR: LA-cp rats during the time frame when insulin resistance develops. At 12 weeks of age, there was a threefold elevation in liver TG content and a sevenfold elevation in skeletal muscle TG content. Hepatic ACC activity was significantly elevated in 12-week-old JCR: LA-cp rats compared with lean age-matched controls (8.75 +/- 0.53 vs. 3.30 +/- 0.18 nmol . min(-1) . mg(-1) respectively), even though AMPK activity was also increased. The observed increase in hepatic ACC activity was accompanied by a 300% increase in ACC protein expression. There were no significant differences in ACC activity, ACC protein expression, or AMPK activity In the skeletal muscle of the 12-week JCR:LA-cp rats. Treatment of 12-week JCR:LA-cp rats with MEDICA 16 (an ATP-citrate lyase inhibitor) resulted in a decrease in hepatic ACC and AMPK activities, but had no effect on skeletal muscle ACC and AMPK. Our data suggest that alterations in ACC or AMPK activity in muscle do not contribute to the development of insulin resistance. However, increased liver ACC activity in the JCR:LA-cp rat appears to contribute to the development of lipid abnormalities, although this increase does not appear to occur secondary to a decrease in AMPK activity.