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

• 批准号: 10678988
• 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
• 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/10678988
• 关键词: 5' -AMP-activated protein kinase; Address; Affect; American; Binding; Biological Assay; Cardiovascular Diseases; Cells; Ceruloplasmin; Chelating Agents; Copper; Data; Development; Diabetes Mellitus; EP300 gene; 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 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

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.

项目摘要 我们的长期目标是了解胰岛素抵抗相关的病理机制。 代谢疾病，特别是非酒精性脂肪性肝病（NAFLD）。虽然NAFLD影响1/4 美国人，并显着增加肝癌和心血管疾病的风险，没有FDA批准 NAFLD治疗目前存在。虽然胰岛素抵抗增加了NAFLD的发病率，但其机制 这些病理学之间的联系尚未完全了解，需要进一步研究。 为了确定介导胰岛素抵抗相关NAFLD的关键因素，我们筛选了糖尿病个体， 血浆蛋白浓度和肝脏基因表达差异的健康对照我们发现， 血浆铜蓝蛋白（CP）是一种肝脏分泌的铜结合蛋白，在糖尿病患者的肝脏和血浆中增加， 患者这些数据与先前发现的高血浆CP浓度的个人， CP与糖尿病或肥胖的严重程度、肥胖、CVD风险和死亡率呈正相关。 此外，我们的初步数据和其他数据表明，人类肝脏CP表达较高， 啮齿类动物NAFLD，而他们的肝脏铜水平低11 -16，与CP的作用，以减少肝脏铜的作用一致。 铜含量然而，高肝CP和低肝铜相关的功能意义 与胰岛素抵抗和NAFLD的关系尚不清楚。 为了解决这一缺陷，我们已经表征了胰岛素抵抗和肝细胞特异性的小鼠模型。 CP删除。这些初步研究表明，以前未认识到的作用，肝CP和铜 胰岛素抵抗和NAFLD的联系。虽然HFD降低肝铜含量并促进NAFLD， 肝特异性敲除或敲除CP（L-CP KO）增加肝铜含量，改变表达 参与肝脏脂质代谢的基因，并改善这些胰岛素抵抗小鼠的NAFLD。我们 假设胰岛素抵抗诱导的肝CP通过破坏铜稳态促进NAFLD， 脂质代谢在目标1中，我们将确定胰岛素抵抗如何诱导肝CP基因转录; 目的2，我们将确定肝CP如何调节铜稳态和NAFLD的发展; 目的3，阐明肝铜稳态失调的分子机制 促进NAFLD。 我们希望完成拟议的研究将确定肝CP和铜在代谢中的作用， 在胰岛素抵抗状态下NAFLD的调节和发展，这可能表明新的治疗方法， NAFLD。

项目成果

Prolonged hypoxia alleviates prolyl hydroxylation-mediated suppression of RIPK1 to promote necroptosis and inflammation.

• DOI: 10.1038/s41556-023-01170-4
• 发表时间: 2023-07
• 期刊: Nature cell biology
• 影响因子: 21.3

Comments on 'Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex'.

• DOI: 10.1093/jmcb/mjad026
• 发表时间: 2023-08-03
• 期刊: Journal of molecular cell biology
• 影响因子: 5.5

Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex.

• DOI: 10.1016/j.celrep.2022.111498
• 发表时间: 2022-10-18
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Xie L;Yuan Y;Xu S;Lu S;Gu J;Wang Y;Wang Y;Zhang X;Chen S;Li J;Lu J;Sun H;Hu R;Piao H;Wang W;Wang C;Wang J;Li N;White MF;Han L;Jia W;Miao J;Liu J
• 通讯作者: Liu J