Insulin regulation of hepatic transport

胰岛素对肝脏运输的调节

基本信息

批准号：
10747550
负责人：
Rebecca Anne Haeusler
金额：
$ 62.19万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-09 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10747550
关键词：
Affect Appearance Basic Science Bile Acid Biosynthesis Pathway Bile Acids Bile fluid Biliary Biology Blood Body Weight decreased Brain Cannulations Cell model Cells Closure by clamp Data Destinations Diazoxide Digestion Distal Dyslipidemias Enterohepatic Circulation Fatty acid glycerol esters Gallbladder Glucose Clamp Grant Health Hepatic Hepatocyte Hormones Hour Human Hyperinsulinism Hypoglycemia Impairment Individual Injections Insulin Insulin Receptor Insulin Resistance Intention Intestines Investigation Kinetics Knock-out Knockout Mice Laboratories Liver Mass Spectrum Analysis Measures Mediating Mediator Metabolic Metabolism Methods Modeling Mus Non obese Nutrient Obese Mice Obesity Operative Surgical Procedures Pancreas Pathway interactions Pharmaceutical Preparations Proteins Proteomics Radiolabeled Receptor Signaling Regulation Serum Signal Transduction Site System Testing Tissues Tracer Work bile acid transporter biomarker validation cytotoxic design diet-induced obesity glucose metabolism human subject in vitro Model in vivo insulin regulation insulin sensitivity insulin signaling lipid metabolism liver function mouse model prevent success uptake

项目摘要

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.

项目概要胆汁酸从血液通过肝脏输送到胆汁是肠肝的基本组成部分有效的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饮食主要协调者的激素我们现在已经证明，这种情况发生在人类、小鼠和小鼠身上。夹心培养的小鼠肝细胞，一种肝脏运输的体外极化模型。肥胖、胰岛素抵抗的人类和小鼠的肝胆汁酸转运受损，这种情况是可以逆转的在这项资助中，我们建议确定该途径的基本生物学原理：通过该途径胰岛素调节胆汁酸转运的上游信号机制？运输最终被用来发挥胰岛素的作用？该途径的哪些方面被破坏了？肥胖/胰岛素抵抗吗？该途径是否影响所有胆汁酸？广泛影响小管分泌？我们将使用金标准胆汁酸动力学研究，高胰岛素- 血糖正常钳、最先进的质谱分析、独特的三明治培养肝细胞模型，以及这项工作的成功有望阐明胰岛素对组织特异性敲除的基本作用。肝功能和餐后营养处理。