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）是全球死亡率的主要原因，强力催化 危险因素是低密度脂蛋白胆固醇（LDL）和甘油三酸酯（TG）的血浆水平升高-Rich 脂蛋白（TRL）。基因组广泛关联研究的强大新颖的血浆研究之一 脂质性状位于包含Trib1基因的染色体基因座8Q24。 Trib1编码假子酶， Trabbles同源1（Trib1），催化性无活性，但已被提议充当适配器和 脚手架蛋白，针对转录因子CEBPα用于泛素化和蛋白体降解。 该基因座的变体与较低的CAD风险，较低的LDL水平，总胆固醇和 TG和有益的高密度脂蛋白（HDL）。小鼠的肝过表达 导致血浆脂质水平和肝脂肪降低，而肝特异性的Trib1缺乏症（Trib1 LSKO） 增加血浆脂质，脂肪生成和肝脂肪变性。必须采用组织特异性方法，因为 在纯C57BL/6背景上的Trib1全身缺失（Trib1 KO）的纯合子的小鼠具有高度 渗透性新生儿致死性。 我的第一个目标是阐明Trib1肝缺乏如何导致小鼠的血浆脂质表型。 血浆脂质受其分泌率和循环清除率之间的平衡来调节； 这两个过程都受肝脏的影响很大。初步数据显示，当LDL清除率降低时 将Trib1 LSKO与对照小鼠进行比较，这表明清除缺陷可以解释表型。 我们以前证明，Cebpa表型肝表达增加了 尊重脂肪生成的增加和肝脂肪变性的发展。但是，仍然未知是否 这也是提高Trib1 LSKO小鼠血浆脂质的因果机制。我的初步数据表明 以肝特异性方式删除CEBPA（CEBPA LSKO）会诱导血浆脂质的减少。我假设 trib1 lsko小鼠中的血浆脂质表型升高是由于CEBPA表达增加 并因LDL清除而受损。我的第二个目标是确定Trib1在调节葡萄糖中的作用 代谢并定义了部落1全身删除导致新生儿的物理机制 死亡。我来自新生儿的初步数据（发电后少于12小时）显示出显着降低 与对照小鼠相比，Trib1缺失的纯合子和杂合的小鼠的血糖水平与对照小鼠相比。 与此相一致，成年Trib1 LSKO小鼠暴露了快速葡萄糖清除率，这与增加 血浆胰岛素水平。我建议检验以下假设：Trib1 Ko小鼠中的新生儿致死性是结果 由于血浆胰岛素水平升高（高胰岛素血症）引起的严重低血糖。 综上所述，拟议的研究将为分子和细胞提供大量的新见解 Trib1调节血浆脂质水平和葡萄糖代谢以及CAD的机制。