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Copper and copper-binding proteins in insulin resistance-associated metabolic disease

胰岛素抵抗相关代谢疾病中的铜和铜结合蛋白

基本信息

批准号：
10502538
负责人：
Ji Miao
金额：
$ 48.43万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-08 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10502538
关键词：
5&apos -AMP-activated protein kinase Address Affect American Binding Binding Proteins Biological Assay Cardiovascular Diseases Cells Ceruloplasmin Chelating Agents Copper Data Development Diabetes Mellitus Etiology FDA approved FOXO1A gene Gene Expression Genes Genetic Transcription Goals Health Hepatic Hepatocyte High Fat Diet Homeostasis Human Incidence Individual Insulin Insulin Resistance Iron Overload Knock-out Knockout Mice Knowledge Link Liver Liver diseases Malignant neoplasm of liver Mediating Membrane Metabolic Metabolic Diseases Molecular Mus Obesity PPAR alpha Pathologic Pathology Phosphotransferases Plasma Plasma Proteins Protein Kinase Protein Kinase Interaction Regulation Risk Rodent Role STK11 gene Severities Signal Transduction Structure of beta Cell of islet Testing Up-Regulation Viral Work blood glucose regulation cardiovascular disorder risk copper-binding protein diabetic diabetic patient fatty acid oxidation improved knock-down lipid metabolism loss of function mortality mouse model mutant non-alcoholic fatty liver disease novel overexpression promoter rational design therapy design

项目摘要

Project Summary Our long-term goal is to understand the pathologic mechanisms underlying insulin resistance-associated metabolic disease, and in particular non-alcoholic fatty liver disease (NAFLD). Although NAFLD affects 1 in 4 Americans and significantly increases the risk of liver cancer and cardiovascular disease, no FDA-approved NAFLD therapies currently exist. Although insulin resistance increases the incidence of NAFLD, the mechanisms linking these pathologies are not completely understood and warrant further study. To identify the key factors mediating insulin resistance-associated NAFLD, we screened diabetic individuals and healthy controls for differences in plasma protein concentrations and hepatic gene expression We found that ceruloplasmin (CP), a liver-secreted copper-binding protein, was increased in the liver and plasma of diabetic patients. These data are consistent with previous findings of high plasma CP concentrations in individuals with diabetes or obesity, and positive correlations of CP with the severity of diabetes, obesity, CVD risk, and mortality. In addition, our preliminary data and data from others show that hepatic CP expression is high in humans and rodents with NAFLD, while their hepatic copper levels are low11-16, consistent with the role of CP to reduce hepatic copper content. However, the functional significance of the high hepatic CP and low hepatic copper associated with insulin resistance and NAFLD is unclear. To address this deficiency, we have characterized mouse models of insulin resistance and hepatocyte-specific CP deletion. These preliminary studies have suggested a previously unrecognized role of hepatic CP and copper in linking insulin resistance and NAFLD. While a HFD decreases hepatic copper content and promotes NAFLD, liver-specific knockdown or knockout of CP (L-CP KO) increases hepatic copper content, alters the expression of genes involved in hepatic lipid metabolism, and ameliorates NAFLD in these insulin resistant mice. We hypothesize that insulin resistance-induced hepatic CP promotes NAFLD by disrupting copper homeostasis and lipid metabolism. In Aim 1, we will determine how insulin resistance induces hepatic CP gene transcription; in Aim 2, we will determine how hepatic CP regulates copper homeostasis and the development of NAFLD; and in Aim 3, we will elucidate the molecular mechanisms by which dysregulation of hepatic copper homeostasis promotes NAFLD. We expect that the completion of the proposed studies will define the role of hepatic CP and copper in metabolic regulation and the development of NAFLD in insulin resistant states, which may suggest new means of treating NAFLD.

项目总结