Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice
Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice
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DOI：
10.1172/jci61919
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发表时间：
2012-04-01
影响因子：
15.9
通讯作者：
Tall, Alan R.
中科院分区：
文献类型：
--
作者：
Ai, Ding;Chen, Chiyuan;Tall, Alan R.
2型糖尿病患者患动脉粥样硬化的风险增加。其中一个潜在的因素是血脂异常，在伴有早期2型糖尿病的高胰岛素患者中，其典型特征是VLDL分泌增加，但LDL胆固醇水平正常，可能反映了LDL通过肝脏ldlr分解代谢增强。最近的研究也表明肝脏胰岛素信号传导维持LDLR水平。因此，我们试图阐明肝胰岛素信号与LDLR水平调节的机制。在WT小鼠中，shRNA敲低胰岛素受体导致肝脏mTORC1信号和LDLR蛋白水平降低。它还导致PCSK9的表达增加，PCSK9是一种已知的LDLR表达的转录后调节因子。mTORC1抑制剂雷帕霉素引起WT小鼠PCSK9表达增加，肝脏LDLR蛋白水平降低，VLDL/LDL胆固醇水平升高，但PCSK9（-/-）小鼠没有。相反，肝脏mTORC1活性升高的小鼠表现出PCSK9表达降低和肝脏LDLR蛋白水平升高。Pcsk9受转录因子HNF1 α的调控，我们进一步的详细分析表明，mTORC1活性的升高导致PKC δ的激活，HNF4 α和HNF1 α活性的降低，Pcsk9表达的降低，最终导致肝脏LDLR蛋白水平升高，从而导致循环LDL水平降低。因此，我们认为PCSK9抑制可能是一种有效的方法，可以减少移植患者接受雷帕霉素作为免疫抑制治疗时LDL水平升高的不良副作用。
Individuals with type 2 diabetes have an increased risk of atherosclerosis. One factor underlying this is dyslipidemia, which in hyperinsulinemic subjects with early type 2 diabetes is typically characterized by increased VLDL secretion but normal LDL cholesterol levels, possibly reflecting enhanced catabolism of LDL via hepatic LDLRs. Recent studies have also suggested that hepatic insulin signaling sustains LDLR levels. We therefore sought to elucidate the mechanisms linking hepatic insulin signaling to regulation of LDLR levels. In WT mice, insulin receptor knockdown by shRNA resulted in decreased hepatic mTORC1 signaling and LDLR protein levels. It also led to increased expression of PCSK9, a known post-transcriptional regulator of LDLR expression. Administration of the mTORC1 inhibitor rapamycin caused increased expression of PCSK9, decreased levels of hepatic LDLR protein, and increased levels of VLDL/LDL cholesterol in WT but not Pcsk9(-/-) mice. Conversely, mice with increased hepatic mTORC1 activity exhibited decreased expression of PCSK9 and increased levels of hepatic LDLR protein levels. Pcsk9 is regulated by the transcription factor HNF1 alpha, and our further detailed analyses suggest that increased mTORC1 activity leads to activation of PKC delta, reduced activity of HNF4 alpha and HNF1 alpha, decreased PCSK9 expression, and ultimately increased hepatic LDLR protein levels, which result in decreased circulating LDL levels. We therefore suggest that PCSK9 inhibition could be an effective way to reduce the adverse side effect of increased LDL levels that is observed in transplant patients taking rapamycin as immunosuppressive therapy.