Insulin regulation of hepatic transport

项目总结 胆汁酸从血液通过肝脏进入胆汁的运输是肠肝的基本部分。 周而复始。有效的经肝转运可防止胆汁酸的细胞毒性作用，对人类健康至关重要。 我们意外地发现，胰岛素，一种长期以来被认为是餐后主奏的荷尔蒙 新陈代谢，促进肝脏胆汁酸的运输。我们现在已经证明，这发生在人类、小鼠和 夹心培养小鼠肝细胞，一种极化的肝转运体外模型。此外，我们发现， 肥胖、胰岛素抵抗的人类和老鼠损害了肝脏胆汁酸的运输，这种情况可以逆转 通过减肥。在这项资助中，我们建议确定这一途径的潜在生物学：通过 上游信号机制胰岛素调节胆汁酸转运吗？胆汁酸的远端介质 运输最终是用来实现胰岛素的效果的吗？这条途径的哪些方面受到干扰 肥胖/胰岛素抵抗？这个途径会影响所有的胆汁酸吗？这种影响是胆汁酸所特有的，还是 广泛影响小管分泌物？我们将使用黄金标准的胆汁酸动力学研究，高胰岛素血症- 正常血糖钳，最先进的质谱仪，独特的三明治培养肝细胞模型，以及 组织特异性基因敲除小鼠。这项工作的成功有望阐明胰岛素对人体健康的根本影响 肝功能和餐后营养处理。

PROJECT SUMMARY Transport of bile acids from blood through the liver into the bile is a fundamental part of the enterohepatic cycle. Efficient transhepatic transport prevents cytotoxic effects of bile acids, and is critical for human health. We have unexpectedly found that insulin, a hormone long known as a chief orchestrator of postprandial metabolism, promotes hepatic bile acid transport. We have now shown that this occurs in humans, mice, and sandwich cultured murine hepatocytes, a polarized in vitro model of hepatic transport. Moreover, we find that obese, insulin resistant humans and mice have impaired hepatic bile acid transport, and this can be reversed by weight loss. In this grant, we propose to determine the underlying biology of this pathway: Through which upstream signaling mechanisms does insulin regulate bile acid transport? Which distal mediators of bile acid transport are ultimately employed to carry out insulin’s effects? Which aspects of this pathway are disrupted in obesity/insulin resistance? Does this pathway affect all bile acids? Is the effect specific to bile acids, or does it broadly affect canalicular secretion? We will use gold-standard bile acid kinetics studies, hyperinsulinemic- euglycemic clamps, state-of-the-art mass spectrometry, unique sandwich cultured hepatocyte models, and tissue-specific knockout mice. Success of this work is expected to elucidate a fundamental effect of insulin on hepatic function and postprandial nutrient handling.