Manmontri Boripont, Sariahmetoglu Meltem, Donkor Jimmy, Bou Khalil Maroun, Sundaram Meenakshi, Yao Zemin, Reue Karen, Lehner Richard, Brindley David N
Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
J Lipid Res. 2008 May;49(5):1056-67. doi: 10.1194/jlr.M800013-JLR200. Epub 2008 Feb 2.
Glucocorticoids (GCs) increase hepatic phosphatidate phosphatase (PAP1) activity. This is important in enhancing the liver's capacity for storing fatty acids as triacylglycerols (TAGs) that can be used subsequently for beta-oxidation or VLDL secretion. PAP1 catalyzes the conversion of phosphatidate to diacylglycerol, a key substrate for TAG and phospholipid biosynthesis. PAP1 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 PAP1 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 PAP1 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 PAP1 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 PAP1 activity, which occurs in hepatic steatosis during starvation, diabetes, stress, and ethanol consumption.
糖皮质激素(GCs)可提高肝脏磷脂酸磷酸酶(PAP1)的活性。这对于增强肝脏将脂肪酸储存为三酰甘油(TAGs)的能力很重要,这些三酰甘油随后可用于β-氧化或极低密度脂蛋白(VLDL)分泌。PAP1催化磷脂酸转化为二酰甘油,二酰甘油是TAG和磷脂生物合成的关键底物。肝脏中的PAP1酶包括脂联素-1A和-1B(可变剪接异构体)以及两种不同的基因产物,脂联素-2和脂联素-3。我们使用大鼠和小鼠肝细胞确定了复合PAP1活性的调节机制。地塞米松(dex;一种合成GC)可增加脂联素-1A和-1B的mRNA水平,这导致脂联素-1合成增加、蛋白质水平升高以及PAP1活性增强。胰高血糖素或cAMP可增强地塞米松对脂联素-1表达的刺激作用,而胰岛素则起拮抗作用。地塞米松/ cAMP不会增加脂联素-2和脂联素-3的mRNA,这表明PAP1活性增加具体归因于脂联素-1表达增强。这项工作为脂联素活性的差异调节提供了首个证据。脂联素-1的选择性表达解释了GC和cAMP对肝脏PAP1活性增加的影响,这种情况发生在饥饿、糖尿病、应激和乙醇摄入期间的肝脂肪变性过程中。