BIOCHEMICAL CAUSES FOR HYPERTRIGLYCERIDEMIA

高甘油三酯血症的生化原因

• 批准号: 2154001
• 负责人: FUMIO none MATSUMURA
• 金额: $ 17.71万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-08-09 至 1996-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2154001
• 关键词: adipose tissue; atherosclerosis; autoradiography; beta adrenergic receptor; biomarker; blood lipoprotein biosynthesis; colorimetry; dioxins; enzyme mechanism; gel electrophoresis; guinea pigs; halobiphenyl /halotriphenyl compound; high performance liquid chromatography; hypertriglyceridemia; lipoprotein lipase; messenger RNA; nucleic acid hybridization; nucleic acid probes; phosphorylation; protein kinase; protein tyrosine kinase; radioimmunoassay; radiotracer; scintillation counter; tissue /cell culture; toxicant interaction; toxin metabolism

Dioxin-type chemicals including PCBs are known to cause acute and chronic hyperlipidemia accompanied with the loss of body fat in several experimental animal species. Not only that most of these chemicals are hardly metabolized by detoxification enzymes and coupled with their extreme lipophilicity, concentrate in the adipose tissues where they remain for a long time period, often for the entire lifespan of the animal. We have previously found that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes significant reduction in the lipoprotein lipase (LPL) levels in the adipose tissue of guinea pigs and rabbits. Such an observation helps to explain why in these species the most predominant toxic expression of TCDD is hypertriglyceridemia. We have also found a number of evidence that TCDD causes early atherosclerosis and reduction in the contraction force of the heart atrial muscles. Since lipid metabolism is known to play a vital role in nutritional homeostasis, and since these dioxin-type chemicals are now commonly found in adipose tissues of various animals including humans, we propose to study this further. In more specific terms, we plan to study (1) acute and chronic effects of TCDD on adipose LPL, synthesis and the ability of the affected adipocytes to respond to high glucose to produce LPL, (2) since TCDD causes a drastic increase in protein kinase activities in the adipose, as in the case of other tissues, characterize the nature of protein kinases, and identify the major substrate proteins for those TCDD affected protein kinases, including insulin and B-adrenergic receptor, (3) establish an in vitro adipocytes system which adequately reproduces the effect of TCDD particularly that on LPL synthesis processes, and (4) by using the knowledge gained by the above studies develop a reliable biomarker to indicate the extent of exposure to hardly metabolizable congeners of PCBs, dioxins and PCDFs. The markers proposed for study are levels of mRNA for LPL, 3H-TCDD binding to the adipocyte nuclear receptor, protein kinase C, protein tyrosine kinase (using antibodies against phosphotyrosine), pp6Olsrc (using specific antibody), and (125)I-insulin binding to its receptor.

已知包括PCB在内的二恶英型化学物质会引起急性和慢性 高脂血症伴随着几个人体内脂肪的损失 实验动物物种。这些化学物质中的大多数不仅是 几乎不被解毒酶代谢，并与它们的极端结合 亲脂性，将其浓缩在脂肪组织中 长时间，通常在整个动物的寿命中。我们有 以前发现2,3,7,8-四氯迪本佐-P-二恶英（TCDD）原因 脂肪中脂蛋白脂肪酶（LPL）水平的显着降低 豚鼠和兔子的组织。这样的观察有助于解释为什么 在这些物种中，TCDD最主要的毒性表达是 高甘油三酯血症。 我们还发现了许多证据表明TCDD 引起早期的动脉粥样硬化和减少的收缩力 心脏心房肌肉。由于已知脂质代谢起着至关重要的作用 在营养稳态中，由于这些二恶英型化学物质为 通常在包括人在内的各种动物的脂肪组织中发现，我们 建议进一步研究。从更具体的角度来看，我们计划研究（1） TCDD对脂肪LPL，合成和能力的急性和慢性作用 在受影响的脂肪细胞中对高葡萄糖产生LPL的反应，（2） 由于TCDD导致蛋白激酶活性的急剧增加 与其他组织一样，脂肪的特征是 蛋白激酶，并鉴定那些TCDD的主要底物蛋白 受影响的蛋白激酶，包括胰岛素和B-肾上腺素受体，（3） 建立一个体外脂肪细胞系统，该系统充分再现 TCD的影响特别是对LPL合成过程的影响，（4） 利用上述研究获得的知识发展可靠 生物标志物表明暴露于几乎无法代谢的程度 PCB，二恶英和PCDF的同源物。提出的研究标记是 LPL，3H-TCDD与脂肪细胞核受体结合的mRNA水平， 蛋白激酶C，蛋白酪氨酸激酶（使用针对的抗体 磷酸酪氨酸），PP6OLSRC（使用特定抗体）和（125）I-胰岛素 与其受体结合。