Branched-chain amino acid deficiency stabilizes insulin-induced vascular
Branched-chain amino acid deficiency stabilizes insulin-induced vascular
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支链氨基酸缺乏可稳定胰岛素诱导的血管
DOI：
10.1002/jcb.24188
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发表时间：
2012
期刊：
影响因子：
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通讯作者：
Ootani M,
中科院分区：
文献类型：
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作者：
Miuma S;Ichikawa T;Arima K;Takeshita S;Muraoka T;Matsuzaki T;Ootani M,
糖代谢异常与包括肝细胞癌（HCC）在内的慢性肝病密切相关。我们以前报道过空腹高胰岛素血症是肝癌患者预后不良的因素。最近的一项大规模研究表明，长期服用支链氨基酸（BCAA）可降低诊断为糖尿病的肥胖患者发生HCC的风险，尽管其机制尚不清楚。在这项研究中，我们分析了高胰岛素培养条件下HepG 2细胞中血管内皮生长因子（VEGF）的表达，并检查了BCAA对VEGF表达的影响。在BCAA缺乏的条件下，200 nM胰岛素显著增加VEGF分泌，但BCAA的加入抑制了VEGF分泌。在高胰岛素培养条件下，BCAA激活mTOR通路并增加HIF-1α的表达，然而定量PCR分析显示，加入BCAA后2 h，胰岛素诱导的VEGF mRNA（VEGF 121和VEGF 165）表达降低。与不存在BCAA相比，存在BCAA时VEGF 121和165 mRNA的半衰期缩短。因此，认为BCAA主要在转录后水平调节VEGF表达。我们还研究了BCAA中的哪些缬氨酸、亮氨酸和异亮氨酸成分对VEGF mRNA的降解至关重要。所有三种BCAA组分都是加速胰岛素诱导的VEGF mRNA降解所必需的。这些结果表明，支链氨基酸的管理可能下调VEGF表达的患者谁有高胰岛素血症，并在发展过程中的肝癌。J.细胞。113：3113-3121，2012.© 2012 Wiley Periodicals，Inc.
Abnormal sugar metabolism is closely related to chronic liver diseases, including hepatocellular carcinoma (HCC). We previously reported that fasting hyperinsulinemia is a poor prognostic factor for HCC patients. A recent large‐scale study has shown that long‐term administration of branched chain amino acids (BCAA) reduces the risk of HCC development in obese cirrhotic patients who have been diagnosed with diabetes mellitus, although the mechanism by which it does so is unclear. In this study, we analyzed the expression of vascular endothelial growth factor (VEGF) in HepG2 cells under high‐insulin culture conditions, and examined the effect of BCAA on VEGF expression. VEGF secretion was significantly increased by 200 nM of insulin under BCAA deficient conditions, but it was repressed by the addition of BCAA. BCAA activated the mTOR pathway and increase HIF‐1α expression under high‐insulin culture conditions, however quantitative PCR analysis showed that insulin‐induced expression of VEGF mRNAs (VEGF121 and VEGF165) decreased 2 h after the addition of BCAA. The half‐lives of both VEGF121 and 165 mRNAs were shortened in the presence of BCAA compared to the absence of BCAA. Therefore it is thought that BCAA regulate VEGF expression mainly at the post‐transcriptional level. We also examined which of the Valine, Leucine, and Isoleucine components of BCAA were essential for VEGF mRNA degradation. All three BCAA components were required for acceleration of insulin‐induced VEGF mRNA degradation. These results suggest that administration of BCAA may downregulate VEGF expression in patients who have hyperinsulinemia and are in the process of developing HCC. J. Cell. Biochem. 113: 3113–3121, 2012. © 2012 Wiley Periodicals, Inc.