AMP-Activated Protein Kinase Suppresses LXR-Dependent Sterol Regulatory Element-Binding Protein-1c Transcription in Rat Hepatoma McA-RH7777 Cells
AMP-Activated Protein Kinase Suppresses LXR-Dependent Sterol Regulatory Element-Binding Protein-1c Transcription in Rat Hepatoma McA-RH7777 Cells
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DOI：
10.1002/jcb.22024
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发表时间：
2009-02-15
影响因子：
4
通讯作者：
Liu, Zhi-Mei
中科院分区：
文献类型：
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作者：
Yang, Jian;Craddock, Lauren;Liu, Zhi-Mei
amp活化蛋白激酶（AMPK）是一种细胞内燃料传感器，在调节肝脏脂肪酸合成中起关键作用。甾醇调节元件结合蛋白(SREBP)-1c是肝脏脂肪生成基因表达的主要调节因子。AMPK激活抑制肝脏SREBP-1 mRNA和细胞核SREBP-1蛋白，这一研究早已被证实。但其机制仍未明确。在这项研究中，我们利用一种新的模型细胞系McA-RH7777研究了AMPK下调肝脏SREBP-1c mRNA的分子机制。我们发现AMPK在两种广泛使用的AMPK激活剂AICAR和二甲双胍处理的大鼠肝癌McA-RH7777细胞中被强烈激活，AMPK的激活急剧抑制SREBP-1c mRNA和核SREBP-1c蛋白，但不抑制来自同一基因的SREBP-I mRNA。这些抑制作用被AMPK抑制剂化合物C或8-BrAMP逆转，证明AMPK在AICAR和二甲双胍抑制SREBP-1c mRNA和核SREBP-1c蛋白中是必需的。在普通转录抑制剂放线菌素D存在的情况下，AMPK不增强SREBP-1c mRNA的降解；相反，在荧光素酶报告基因试验中，它抑制SREBP-1c启动子活性。AMPK介导的对SREBP-1c启动子活性的抑制也可以被AMPK抑制剂化合物c所消除。此外，AMPK的激活显著减弱了合成肝X受体（LXR）配体t0901317诱导的SREBP-1c启动子活性。AMPK还抑制LXR配体诱导的SREBP-1c前体的裂解。我们得出结论，AMPK通过抑制内源性LXR配体的产生和抑制McA-RH7777细胞中SREBP-1c的加工，抑制LXR依赖性SREBP-1c的转录，从而抑制肝脏SREBP-1c mRNA的表达。j .细胞。生物化学学报，26(6):414-426,2009。(C) 2009 Wiley-Liss, Inc。
AMP-activated protein kinase (AMPK) is an intracellular fuel sensor that plays a key role in regulating fatty acid synthesis in liver. Sterol regulatory element-binding protein (SREBP)-1c is a master regulator of hepatic lipogenic gene expression. It has long been documented that AMPK activation suppresses hepatic SREBP-1 mRNA and nuclear SREBP-I protein. But the mechanism remains undefined. In this study we investigated the molecular mechanisms by which AMPK downregulates hepatic SREBP-1c mRNA using a novel model cell line McA-RH7777. We found that AMPK is robustly activated in rat hepatoma McA-RH7777 cells treated with two widely used AMPK activators, AICAR and metformin, and AMPK activation sharply suppresses SREBP-1c mRNA and nuclear SREBP-1c protein, but not SREBP-I a mRNA derived from the same gene. These inhibitory effects are reversed by the AMPK inhibitor Compound C or 8-BrAMP, demonstrating the requirement of AMPK in the suppression of SREBP-1c mRNA and nuclear SREBP-1c protein by AICAR and metformin. AMPK does not enhance SREBP-1c mRNA degradation in the presence of the general transcription inhibitor actinomycin D; instead it inhibits SREBP-1c promoter activity in a luciferase reporter assay. AMPK-mediated inhibition of SREBP-1c promoter activity can also be abrogated by the AMPK inhibitor Compound C. Furthermore AMPK activation significantly attenuates the synthetic liver X receptor (LXR) ligand T0901317-induced SREBP-1c promoter activity. AMPK also inhibits cleavage of LXR ligand-induced SREBP-1c precursor. We conclude that AMPK suppresses hepatic SREBP-1c mRNA expression by inhibiting LXR-dependent SREBP-1c transcription via inhibition of endogenous LXR ligand production and by inhibiting SREBP-1c processing in McA-RH7777 cells. J. Cell. Biochem. 106: 414-426, 2009. (C) 2009 Wiley-Liss, Inc.