Inhibition of net HepG2 cell apolipoprotein B secretion by the citrus flavonoid naringenin involves activation of phosphatidylinositol 3-kinase, independent of insulin receptor substrate-1 phosphorylation
Inhibition of net HepG2 cell apolipoprotein B secretion by the citrus flavonoid naringenin involves activation of phosphatidylinositol 3-kinase, independent of insulin receptor substrate-1 phosphorylation
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DOI：
10.2337/diabetes.52.10.2554
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发表时间：
2003-10-01
期刊：
影响因子：
7.7
通讯作者：
Huff, MW
中科院分区：
文献类型：
--
作者：
Borradaile, NM;de Dreu, LE;Huff, MW
类黄酮柚皮素可改善链脲佐菌素治疗大鼠的高脂血症和高血糖症。在 HepG2 人肝癌细胞中，柚皮素主要通过抑制微粒体甘油三酯转移蛋白来抑制载脂蛋白 B (apoB) 分泌，并增强 LDL 受体 (LDLr) 介导的含 apoB 脂蛋白的摄取。胰岛素激活磷脂酰肌醇 3 激酶 (PI3K) 会增加甾醇调节元件结合蛋白 (SREBP)-1 和 LDLr 的表达，并抑制肝细胞中 apoB 的分泌。因此，我们确定柚皮素是否激活该途径。胰岛素和柚皮素诱导 PI3K 依赖性细胞质和细胞核 SREBP-1 和 LDLr 表达的增加。在主要表达 SREBP-1c 的 McA-RH7777 大鼠肝癌细胞中观察到类似的 PI3K 介导的 SREBP-1 增加。含有柚皮素的 HepG2 细胞培养基 apoB 的减少被渥曼青霉素部分减弱，而胰岛素的作用被完全阻断。两种治疗均以相同程度减少野生型和 LDLr-/- 小鼠肝细胞中 apoB100 的分泌。胰岛素和柚皮素增加 HepG2 细胞 PI3K 活性并降低胰岛素受体底物 (IRS)-2 水平。与胰岛素形成鲜明对比的是，柚皮素不诱导 IRS-1 的酪氨酸磷酸化。我们得出结论，柚皮素通过 PI3K 介导的 SREBP-1 上调增加 HepG2 细胞中 LDLr 的表达，与 IRS-1 磷酸化无关。尽管该途径可能无法调节原代肝细胞中的 apoB 分泌，但通过这种新机制激活 PI3K 可以解释柚皮素在体内的胰岛素样作用。
The flavonoid naringenin improves hyperlipidemia and hyperglycemia in streptozotocin-treated rats. In HepG2 human hepatoma cells, naringenin inhibits apolipoprotein B (apoB) secretion primarily by inhibiting microsomal triglyceride transfer protein and enhances LDL receptor (LDLr)-mediated apoB-containing lipoprotein uptake. Phosphatidylinositol 3-kinase (PI3K) activation by insulin increases sterol regulatory element-binding protein (SREBP)-1 and LDLr expression and inhibits apoB secretion in hepatocytes. Thus, we determined whether naringenin activates this pathway. Insulin and naringenin induced PI3K-dependent increases in cytosolic and nuclear SREBP-1 and LDLr expression. Similar PI3K-mediated increases in SREBP-1 were observed in McA-RH7777 rat hepatoma cells, which express predominantly SREBP-1c. Reductions in HepG2 cell media apoB with naringenin were partially attenuated by wortmannin, whereas the effect of insulin was completely blocked. Both treatments reduced apoB100 secretion in wild-type and LDLr-/- mouse hepatocytes to the same extent. Insulin and naringenin increased HepG2 cell PI3K activity and decreased insulin receptor substrate (IRS)-2 levels. In sharp contrast to insulin, naringenin did not induce tyrosine phosphorylation of IRS-1. We conclude that naringenin increases LDLr expression in HepG2 cells via PI3K-mediated upregulation of SREBP-1, independent of IRS-1 phosphorylation. Although this pathway may not regulate apoB secretion in primary hepatocytes, PI3K activation by this novel mechanism may explain the insulin-like effects of naringenin in vivo.