Glucocorticoids and cyclic AMP selectively increase hepatic lipin-1 expression, and insulin acts antagonistically
Glucocorticoids and cyclic AMP selectively increase hepatic lipin-1 expression, and insulin acts antagonistically
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DOI：
10.1194/jlr.m800013-jlr200
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发表时间：
2008-05-01
影响因子：
6.5
通讯作者：
Brindley, David N.
中科院分区：
文献类型：
--
作者：
Manmontri, Boripant;Sariahmetoglu, Meltem;Brindley, David N.
糖皮质激素 (GC) 会增加肝磷脂酸磷酸酶 (PAPI) 的活性。这对于增强肝脏将脂肪酸储存为三酰甘油 (TAG) 的能力非常重要，而甘油三酯随后可用于 P-氧化或 VLDL 分泌。 PAN 催化磷脂酸转化为二酰基甘油，二酰基甘油是 TAG 和磷脂生物合成的关键底物。肝脏中的 PAPI 酶包括 lipin-1A 和 -1B（选择性剪接异构体）以及两种不同的基因产物 lipin-2 和 lipin-3。我们利用大鼠和小鼠肝细胞确定了复合 PAPI 活性的调节机制。地塞米松（dex；一种合成 GC）可增加 lipin-1A 和 -1B mRNA 的水平，从而导致 lipin-1 合成、蛋白质水平和 PAPI 活性增加。 dex 对 lipin-1 表达的刺激作用可被胰高血糖素或 cAMP 增强，并被胰岛素拮抗。 dex/cAMP 不会增加 Lipin-2 和 lipin-3 mRNA，表明 PAPI 活性的增加具体归因于 lipin-1 表达的增强。这项工作为脂质活性的差异调节提供了第一个证据。选择性 lipin-1 表达解释了 GC 和 cAMP 对肝脏 PAPI 活性增加的影响，这种活性发生在饥饿、糖尿病、压力和乙醇消耗期间的肝脏脂肪变性中。
Glucocorticoids (GCs) increase hepatic phosphatidate phosphatase (PAPI) activity. This is important in enhancing the liver's capacity for storing fatty acids as triacylglycerols (TAGs) that can be used subsequently for P-oxidation or VLDL secretion. PAN catalyzes the conversion of phosphatidate to diacylglycerol, a key substrate for TAG and phospholipid biosynthesis. PAPI enzymes in liver include lipin-1A and -1B (alternatively spliced isoforms) and two distinct gene products, lipin-2 and lipin-3. We determined the mechanisms by which the composite PAPI activity is regulated using rat and mouse hepatocytes. Levels of lipin-1A and -1B mRNA were increased by dexamethasone (dex; a synthetic GC), and this resulted in increased lipin-1 synthesis, protein levels, and PAPI activity. The stimulatory effect of dex on lipin-1 expression was enhanced by glucagon or cAMP and antagonized by insulin. Lipin-2 and lipin-3 mRNA were not increased by dex/cAMP, indicating that increased PAPI activity is attributable specifically to enhanced lipin-1 expression. This work provides the first evidence for the differential regulation of lipin activities. Selective lipin-1 expression explains the GC and cAMP effects on increased hepatic PAPI activity, which occurs in hepatic steatosis during starvation, diabetes, stress, and ethanol consumption.