Protein kinase A suppresses sterol regulatory element-binding protein-1C expression via phosphorylation of liver X receptor in the liver
Protein kinase A suppresses sterol regulatory element-binding protein-1C expression via phosphorylation of liver X receptor in the liver
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DOI：
10.1074/jbc.m611911200
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发表时间：
2007-04-20
影响因子：
4.8
通讯作者：
Yamada, Nobuhiro
中科院分区：
文献类型：
--
作者：
Yamamoto, Takashi;Shimano, Hitoshi;Yamada, Nobuhiro
固醇调节元件结合蛋白（SREBP）-1c是一种转录因子，控制肝脏中脂肪酸和甘油三酯的合成，并受营养和激素的高度调节。在目前的研究中，我们发现蛋白激酶A（PKA），胰高血糖素/cAMP的介质，空腹信号，通过调节肝脏X受体α（LXR α）的活性抑制SREBP-1c，SREBP-1c表达的主要激活剂。PKA的激活抑制了LXR诱导的大鼠原代肝细胞和小鼠肝脏中SREBP-1c的表达。启动子分析表明，SREBP-1c启动子中的LXR α结合位点负责PKA对SREBP-1c转录的抑制作用。在体外和体内，PKA直接磷酸化LXR α，其配体结合/异源二聚化结构域中的两个共有PKA靶位点（195，196丝氨酸和290，291丝氨酸）对于抑制LXR信号传导至关重要。LXR α的PKA磷酸化通过阻止LXR α/RXR二聚化导致DNA结合活性受损，并通过抑制辅激活因子SCR-1的募集和增强辅阻遏因子NcoR 1的募集降低其转录活性。这些结果表明，LXR α不仅受到氧固醇衍生物的调节，而且还受到PKA介导的磷酸化的调节，这表明SREBP-1c和脂肪生成的营养调节至少部分地可以通过LXR的调节来调节。
Sterol regulatory element-binding protein ( SREBP)-1c is a transcription factor that controls synthesis of fatty acids and triglycerides in the liver and is highly regulated by nutrition and hormones. In the current studies we show that protein kinase A ( PKA), a mediator of glucagon/cAMP, a fasting signaling, suppresses SREBP-1c by modulating the activity of liver X receptor alpha( LXR alpha), a dominant activator of SREBP-1c expression. Activation of PKA repressed LXR-induced SREBP-1c expression both in rat primary hepatocytes and mouse livers. Promoter analyses revealed that the LXR alpha-binding site in the SREBP-1c promoter is responsible for PKA inhibitory effect on SREBP-1c transcription. In vitro and in vivo PKA directly phosphorylated LXR alpha, and the two consensus PKA target sites ( 195, 196 serines and 290, 291 serines) in its ligand binding/heterodimerization domain were crucial for the inhibition of LXR signaling. PKA phosphorylation of LXR alpha caused impaired DNA binding activity by preventing LXR alpha/RXR dimerization and decreased its transcription activity by inhibiting recruitment of coactivator SCR-1 and enhancing recruitment of corepressor NcoR1. These results indicate that LXR alpha is regulated not only by oxysterol derivatives but also by PKA-mediated phosphorylation, which suggests that nutritional regulation of SREBP-1c and lipogenesis could be regulated at least partially through modulation of LXR.