FoxO3 Transcription Factor and Sirt6 Deacetylase Regulate Low Density Lipoprotein (LDL)-cholesterol Homeostasis via Control of the Proprotein Convertase Subtilisin/Kexin Type 9 (Pcsk9) Gene Expression
FoxO3 Transcription Factor and Sirt6 Deacetylase Regulate Low Density Lipoprotein (LDL)-cholesterol Homeostasis via Control of the Proprotein Convertase Subtilisin/Kexin Type 9 (Pcsk9) Gene Expression
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DOI：
10.1074/jbc.m113.481473
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发表时间：
2013-10-11
影响因子：
4.8
通讯作者：
Dong, X. Charlie
中科院分区：
文献类型：
--
作者：
Tao, Rongya;Xiong, Xiwen;Dong, X. Charlie
LDL-胆固醇升高是心血管疾病发展的危险因素。因此，适当控制LDL-胆固醇稳态对生物体健康至关重要。遗传分析已经确定PCSK 9（前蛋白转化酶枯草杆菌蛋白酶/kexin 9型）是通过控制LDL受体降解来调节LDL-胆固醇的关键基因。虽然PCSK 9的生化特征和临床意义已被广泛研究，但该基因的表观遗传调控在很大程度上是未知的。在这项工作中，我们发现Sirt 6，一种NAD（+）依赖性组蛋白脱乙酰酶，在小鼠Pcsk 9基因表达的调节中起着关键作用。肝脏Sirt 6缺乏导致Pcsk 9基因表达和LDL-胆固醇升高。从机制上讲，我们已经证明，Sirt 6可以招募叉头转录因子FoxO 3的近端启动子区的Pcsk 9基因和脱乙酰组蛋白H3的赖氨酸9和56，从而抑制基因的表达。同样值得注意的是，Sirt 6在高脂肪饮食喂养的小鼠中的过表达降低了LDL-胆固醇。总的来说，我们的数据表明，FoxO 3和Sirt 6这两个长寿基因可以通过调节Pcsk 9基因来降低LDL胆固醇水平。
Elevated LDL-cholesterol is a risk factor for the development of cardiovascular disease. Thus, proper control of LDL-cholesterol homeostasis is critical for organismal health. Genetic analysis has identified PCSK9 (proprotein convertase subtilisin/kexin type 9) as a crucial gene in the regulation of LDL-cholesterol via control of LDL receptor degradation. Although biochemical characteristics and clinical implications of PCSK9 have been extensively investigated, epigenetic regulation of this gene is largely unknown. In this work we have discovered that Sirt6, an NAD(+)-dependent histone deacetylase, plays a critical role in the regulation of the Pcsk9 gene expression in mice. Hepatic Sirt6 deficiency leads to elevated Pcsk9 gene expression and LDL-cholesterol as well. Mechanistically, we have demonstrated that Sirt6 can be recruited by forkhead transcription factor FoxO3 to the proximal promoter region of the Pcsk9 gene and deacetylates histone H3 at lysines 9 and 56, thereby suppressing the gene expression. Also remarkably, overexpression of Sirt6 in high fat diet-fed mice lowers LDL-cholesterol. Overall, our data suggest that FoxO3 and Sirt6, two longevity genes, can reduce LDL-cholesterol levels through regulation of the Pcsk9 gene.