Mechanisms by which Trib1 regulates plasma lipids and glucose metabolism

Trib1 调节血脂和葡萄糖代谢的机制

• 批准号: 9766102
• 负责人: Katherine Quiroz-Figueroa
• 金额: $ 4.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766102
• 关键词: 8q24; Adaptor Signaling Protein; Adipose tissue; Adult; Affect; Biological; Biomedical Research; Birth; Blood Circulation; Blood Glucose; Cause of Death; Cholesterol; Chromosomes; Coronary Arteriosclerosis; Data; Defect; Development; Disease Progression; Enterobacteria phage P1 Cre recombinase; Equilibrium; Etiology; Exhibits; Fatty Liver; Fatty acid glycerol esters; Gene Proteins; Genes; Genetic; Glucose; Goals; Health; Hepatic; High Density Lipoproteins; Homologous Gene; Hour; Human; Human Genetics; Hyperinsulinism; Hypoglycemia; Impairment; Injections; Insulin; Knockout Mice; LDL Cholesterol Lipoproteins; Lead; Lipids; Lipoproteins; Liver; Measures; Metabolic; Metabolic Clearance Rate; Metabolism; Modeling; Molecular; Molecular Probes; Mus; Neonatal; Pancreas; Pathway interactions; Pharmaceutical Preparations; Phenocopy; Phenotype; Physiological; Plasma; Postpartum Period; Process; Proteins; Regulation; Risk Factors; Role; Scaffolding Protein; Skeletal Muscle; System; Techniques; Testing; Tissues; Training; Triglycerides; Ubiquitination; Variant; Wild Type Mouse; Work; blood glucose regulation; career; cohort; disorder risk; experimental study; genetic variant; genome wide association study; glucose metabolism; improved; in vivo; insight; intraperitoneal; lipid biosynthesis; lipid metabolism; lipoprotein triglyceride; low density lipoprotein triglyceride; mortality; neonatal death; neonate; novel; overexpression; postnatal; pup; therapeutic target; trait; transcription factor

Project Summary Coronary artery disease (CAD) is the leading cause of mortality worldwide, for which the strongest causal risk factors are elevated plasma levels of low-density lipoprotein cholesterol (LDL) and triglyceride (TG)-rich lipoproteins (TRL). One of the strongest novel loci identified by genome wide association studies for plasma lipid traits is at chromosomal locus 8q24, which contains the TRIB1 gene. TRIB1 encodes the pseudokinase, Tribbles homolog 1 (TRIB1) which is catalytically inactive, but has been proposed to act as an adaptor and scaffolding protein, targeting the transcription factor CEBPα for ubiquitination and proteosomal degradation. Variants at this locus in humans are associated with lower CAD risk, lower levels of LDL, total cholesterol and TG, and beneficially, higher levels of high-density lipoproteins (HDL). Hepatic overexpression of Trib1 in mice results in decreased plasma lipid levels and hepatic fat, while hepatic-specific Trib1 deficiency (Trib1 LSKO) increases plasma lipids, lipogenesis and hepatic steatosis. A tissue-specific approach was necessary because mice homozygous for Trib1 whole body deletion (Trib1 KO) on a pure C57BL/6 background have a highly penetrant neonatal lethality. My first goal is to elucidate how Trib1 hepatic deficiency leads to the plasma lipid phenotype in mice. Plasma lipids are regulated by the balance between their rates of secretion and clearance from circulation; both processes heavily influenced by the liver. Preliminary data shows decreased LDL clearance rate when comparing Trib1 LSKO with control mice, suggesting that a defect in clearance could explain the phenotype. We previously demonstrated that increased hepatic expression of Cebpa phenocopies Trib1 LSKO with respect to increased lipogenesis and the development of hepatic steatosis. However, it is still unknown if this is also the causal mechanism for increased plasma lipid in Trib1 LSKO mice. My preliminary data shows that deleting Cebpa in a liver specific manner (Cebpa LSKO) induces a decrease in plasma lipids. I hypothesize that the elevated plasma lipid phenotype in Trib1 LSKO mice is due to increase in Cebpa expression and by impaired LDL clearance. My second goal is to determine the roles of Trib1 in regulating glucose metabolism and to define the physiological mechanism by which Trib1 whole body deletion leads to neonatal death. My preliminary data from neonates (less than 12 hours post-partum) shows a significant reduction in blood glucose levels in mice homozygous and heterozygous for the Trib1 deletion compared to control mice. Consistent with this, adult Trib1 LSKO mice exhibit rapid glucose clearance, which correlates with increased plasma insulin levels. I propose to test the hypothesis that neonatal lethality in Trib1 KO mice is results from severe hypoglycemia due to increased plasma insulin levels (hyperinsulinemia). Taken together, the proposed studies will provide substantial new insight into the molecular and cellular mechanisms by which Trib1 modulates plasma lipid levels and glucose metabolism, as well as CAD.

项目摘要 冠状动脉疾病(CAD)是世界范围内导致死亡的主要原因，其最主要的原因是 危险因素是血浆低密度脂蛋白胆固醇和富含甘油三酯的水平升高 脂蛋白(TRL)。全基因组关联研究确定的最强的血浆新基因座之一 脂肪性状位于染色体8q24上，含有TRIB1基因。TRIB1编码伪激酶， Tribble同系物1(TRIB1)，催化不活跃，但已被提出作为接头和 支架蛋白，靶向转录因子CEBPα泛素化和蛋白酶体降解。 人类该基因座的变异与较低的冠心病风险、较低的低密度脂蛋白、总胆固醇和 甘油三酯，有益的是，更高水平的高密度脂蛋白(HDL)。Trib1基因在小鼠肝脏中的过表达 导致血脂水平和肝脏脂肪降低，而肝脏特异性Trib1缺乏症(Trib1 LSKO) 增加血脂、脂肪生成和肝脏脂肪变性。组织特异性方法是必要的，因为 在纯C57BL/6背景上具有Trib1全身缺失(Trib1 KO)纯合子的小鼠具有高度的 穿透性新生儿死亡率。 我的第一个目标是阐明Trib1肝脏缺陷如何导致小鼠的血脂表型。 血浆脂类受其分泌速率和循环清除速率之间的平衡调节； 这两个过程都受到肝脏的严重影响。初步数据显示，当 将Trib1 LSKO与对照组小鼠进行比较，表明清除缺陷可以解释这种表型。 我们先前证明了CEBPA表型Trib1 LSKO在肝脏的表达增加 关于脂肪生成增加和肝脏脂肪变性的发展。然而，目前还不清楚这是不是 也是导致Trib1 LSKO小鼠血脂升高的原因机制。我的初步数据显示 以肝脏特异性方式删除CEBPA(CEBPA LSKO)可导致血脂降低。我假设 Trib1 LSKO小鼠血脂表型升高与CEBPA表达增加有关 以及低密度脂蛋白清除受损。我的第二个目标是确定Trib1在调节血糖中的作用 代谢和确定Trib1全身缺失导致新生儿的生理机制 死亡。我对新生儿(产后不到12小时)的初步数据显示， 与对照组相比，Trib1缺失纯合子和杂合子小鼠的血糖水平。 与此一致的是，成年Trib1 LSKO小鼠表现出快速的葡萄糖清除，这与 血浆胰岛素水平。我建议检验这样一种假设，即Trib1 KO小鼠的新生儿死亡率是 由于血浆胰岛素水平升高而导致的严重低血糖(高胰岛素血症)。 综上所述，拟议的研究将为分子和细胞提供实质性的新见解。 Trib1调节血脂水平和葡萄糖代谢的机制，以及CAD。