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Bile acids and insulin sensitivity

胆汁酸和胰岛素敏感性

基本信息

批准号：
10221090
负责人：
Rebecca Anne Haeusler
金额：
$ 18.91万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10221090
关键词：
3-Dimensional Acids Address Adult Agonist Atherosclerosis Bile Acids Bile fluid Biochemical Blood Body Weight Body Weight decreased Carbon Cardiovascular Diseases Cholesterol Complications of Diabetes Mellitus Data Development Diabetes Mellitus Diet Dietary Fats Energy Metabolism Enterohepatic Circulation Enzymes Face Fatty Liver Fatty acid glycerol esters G-Protein-Coupled Receptors GPBAR1 gene GTP-Binding Protein alpha Subunits, Gs Genetic Glucose Hepatic Hepatocyte High Fat Diet Human Hyperglycemia Hypertriglyceridemia Insulin Insulin Resistance Intestines Knock-out Leptin Lipids Liver Liver diseases Low-Density Lipoproteins Metabolic Metabolic Diseases Metabolic Pathway Metabolic dysfunction Modeling Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Obese Mice Obesity Organoids Pathway interactions Patients Pattern Pharmacology Phase III Clinical Trials Physiology Positioning Attribute Role Signal Pathway Signal Transduction Testing Thinness Tissues Villus Weight Gain absorption base cardioprotection cell type chemical genetics diabetic genetic manipulation glucose metabolism hydroxyl group improved in vivo induced pluripotent stem cell insulin sensitivity insulin sensitizing drugs insulin signaling knock-down lipid metabolism new therapeutic target nonalcoholic steatohepatitis novel novel therapeutic intervention oral glucose tolerance patient population phase II trial prevent receptor stem cells tool

项目摘要

PROJECT SUMMARY Bile acid (BA) signaling pathways are plausible new therapeutic targets for metabolic disease. One potential approach is to improve the composition of endogenous BAs. Humans have dozens of species of BAs, and each is differently able to carry out BA functions. We have previously identified a subset of BAs–those containing a hydroxyl group at the carbon 12 position–that are regulated by hepatic insulin signaling, increased in human insulin resistance, and correlated with metabolic dysfunctions. Eliminating 12-hydroxy BAs by ablating the enzyme required for their synthesis, Cyp8b1, lowers body weight, lipids, and glucose. However the molecular mechanisms of these improvements are incompletely understood, particularly the mechanisms leading to improved glycemia. Thus we have identified three fundamental, unanswered questions for our studies: First, what signaling pathways are required to bring about these improvements? Second, what are the direct effects of 12-hydroxy BAs on cellular metabolic and signaling cascades? Third, what are the metabolic benefits of eliminating 12-hydroxy BAs in pre-existing diabetes/obesity? These questions will be addressed in vivo and ex vivo, using genetic, biochemical, and humanized tools. The proposed studies will improve our understanding of this conserved enzyme in physiology and its potential as a new therapeutic strategy.

项目总结