Heparin-Binding EGF-Like Growth Factor (HB-EGF) Mediates 5-HT-Induced Insulin Resistance Through Activation of EGF Receptor-ERK1/2-mTOR Pathway
Heparin-Binding EGF-Like Growth Factor (HB-EGF) Mediates 5-HT-Induced Insulin Resistance Through Activation of EGF Receptor-ERK1/2-mTOR Pathway
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DOI：
10.1210/en.2011-1418
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发表时间：
2012-01-01
期刊：
影响因子：
4.8
通讯作者：
Funaki, Makoto
中科院分区：
文献类型：
--
作者：
Li, Qinkai;Hosaka, Toshio;Funaki, Makoto
虽然胰岛素敏感性与Gq/11偶联受体激动剂（如内皮素-1、凝血酶和5-羟色胺（5-HT））水平呈负相关，但其确切机制仍不清楚。在这份报告中，我们提供的证据表明，5-HT诱导生产肝素结合表皮生长因子样生长因子（HB-EGF），并导致胰岛素抵抗的3 T3-L1脂肪细胞，原代脂肪细胞和C2 C12肌管。在3 T3-L1脂肪细胞中，5-HT通过促进跨膜蛋白pro-HB-EGF的金属蛋白酶依赖性脱落来刺激HB-EGF的产生。然后HB-EGF结合并酪氨酸磷酸化EGF受体，其通过ERK 1/2磷酸化激活雷帕霉素通路的哺乳动物靶点。雷帕霉素激活的哺乳动物靶点引起胰岛素受体底物-1的丝氨酸磷酸化，从而减弱胰岛素刺激的胰岛素受体底物-1的酪氨酸磷酸化和葡萄糖摄取。药理学抑制Gq/11偶联受体或金属蛋白酶，以及抑制或敲低HB-EGF或G α q/11，恢复5-HT受损的胰岛素信号转导。金属蛋白酶活性的抑制也消除了HB-EGF的生产和随后的EGF受体激活的其他Gq/11偶联受体激动剂已知会导致胰岛素抵抗，如内皮素-1和凝血酶。这些结果表明，通过HB-EGF加工的EGF受体的反式激活在5-HT诱导的胰岛素抵抗中起着关键作用。（内分泌学153：56-68，2012）
Although an inverse correlation between insulin sensitivity and the level of Gq/11-coupled receptor agonists, such as endothelin-1, thrombin, and 5-hydroxytryptamine (5-HT), has been reported, its precise mechanism remains unclear. In this report, we provide evidence that 5-HT induced production of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and caused insulin resistance in 3T3-L1 adipocytes, primary adipocytes, and C2C12 myotubes. In 3T3-L1 adipocytes, 5-HT stimulated HB-EGF production by promoting metalloproteinase-dependent shedding of transmembrane protein pro-HB-EGF. HB-EGF then bound and tyrosine-phosphorylated EGF receptors, which activated the mammalian target of rapamycin pathway through ERK1/2 phosphorylation. Mammalian target of rapamycin activation caused serine phosphorylation of insulin receptor substrate-1, which attenuated insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 and glucose uptake. Pharmacological inhibition of either Gq/11-coupled receptors or metalloproteinases, as well as either inhibition or knockdown of HB-EGF or G alpha q/11, restored insulin signal transduction impaired by 5-HT. Inhibition of metalloproteinase activity also abolished HB-EGF production and subsequent EGF receptor activation by other Gq/11-coupled receptor agonists known to cause insulin resistance, such as endothelin-1 and thrombin. These results suggest that transactivation of the EGF receptor through HB-EGF processing plays a pivotal role in 5-HT-induced insulin resistance. (Endocrinology 153: 56-68, 2012)