Distinct roles of insulin and liver X receptor in the induction and cleavage of sterol regulatory element-binding protein-1c
Distinct roles of insulin and liver X receptor in the induction and cleavage of sterol regulatory element-binding protein-1c
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DOI：
10.1073/pnas.0405067102
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发表时间：
2005-01-18
影响因子：
11.1
通讯作者：
Foufelle, F
中科院分区：
文献类型：
--
作者：
Hegarty, BD;Bobard, A;Foufelle, F
固醇调节元件结合蛋白（SREBP）是调节脂质代谢的核心转录因子。SREBP作为前体蛋白合成，其需要蛋白水解加工以变得具有转录活性。尽管细胞固醇含量对SREBP-1a和-2裂解的调节是明确的，但对SREBP-1c（肝脏中主要的SREBP同种型）的调节知之甚少。胰岛素和肝脏X受体α（LXR α）均诱导SREBP-1c转录;然而，这些因子各自的作用以及负责该SREBP亚型蛋白水解裂解的机制尚不清楚。在这项研究中，我们比较了胰岛素和LXR激动剂TO 901317对SREBP-1c的表达和转录活性在离体大鼠肝细胞的影响。我们报告说，SREBP-1c蛋白的成熟和转录活性形式的完全诱导需要胰岛素。尽管LXR的激活导致SREBP-1c基因表达和前体蛋白的诱导，但其在诱导转录因子的成熟核形式方面具有非常差的效果。这可能是由于LXR激活对胰岛素诱导的基因-2a mRNA和蛋白质的诱导。然而，LXR诱导的SREBP-1c前体在急性暴露于胰岛素时通过磷脂酰肌醇3-激酶依赖性机制迅速裂解。最后，我们通过在乳鼠中的实验表明，胰岛素刺激SREBP-1c的蛋白水解加工的这种急性作用在体内是有功能的。
Sterol regulatory element-binding proteins (SREBPs) are transcription factors central to the regulation of lipid metabolism. The SREBPs are synthesized as precursor proteins that require proteolytic processing to become transcriptionally active. Whereas the regulation of SREBP-1a and -2 cleavage by cellular sterol content is well defined, much less is known about the regulation of SREBP-1c, the predominant SREBP isoform in the liver. Both insulin and liver X receptor alpha (LXRalpha) induce SREBP-1c transcription; however, the respective roles of these factors and the mechanism responsible for proteolytic cleavage of this SREBP isoform are not known. In this study, we compare the effects of insulin and LXR agonist TO901317 on SREBP-1c expression and transcriptional activity in isolated rat hepatocytes. We report that full induction of the mature and transcriptionally active form of SREBP-1c protein requires insulin. Although activation of LXR leads to the induction of SREBP-1c gene expression and precursor protein, it has a very poor effect in inducing the mature nuclear form of the transcription factor. This may be due to the induction of insulin-induced gene-2a mRNA and protein by LXR activation. The LXR-induced SREBP-1c precursor, however, is rapidly cleaved on acute exposure to insulin via a phosphatidylinositol 3-kinase-dependent mechanism. Finally, we show through experiments in suckling mice that this acute action of insulin to stimulate the proteolytic processing of SREBP-1c is functional in vivo.