Insulin regulation of hepatic transport

项目摘要 胆汁酸从血液通过肝脏转运到胆汁中是肝肠功能的基本部分。 周期有效的跨膜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要协调者的激素， 代谢，促进肝胆汁酸转运。我们现在已经证明，这发生在人类，小鼠， 夹心培养的鼠肝细胞，一种极化的体外肝转运模型。此外，我们发现， 肥胖、胰岛素抵抗的人类和小鼠的肝脏胆汁酸转运受损，这是可以逆转的 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： 上游信号机制胰岛素调节胆汁酸转运？哪种胆汁酸的远端介质 运输最终是用来实现胰岛素的作用的？这条通路的哪些方面在 肥胖/胰岛素抵抗？这种途径影响所有的胆汁酸吗？这种效应是胆汁酸特有的吗 广泛影响泪小管分泌吗我们将使用金标准胆汁酸动力学研究，高胰岛素血症- 正葡萄糖钳夹、最先进的质谱、独特的夹心培养肝细胞模型，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糖尿病的基本作用。 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.