Analysis of the etiology of hyperlipoproteinemia (a) and transcriptional regulation of apolipoprotein (a).

高脂蛋白血症的病因分析(a)和载脂蛋白的转录调控(a)。

• 批准号: 06671002
• 负责人: MATSUSHIMA Teruhiko
• 金额: $ 1.28万
• 依托单位: University of Tsukuba
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06671002/
• 关键词: lipoprotein (a); apolipoprotein (a); diabetes mellitus; hemodiasysis; mRNA; transcription; interleukin-6; insulin; lipoproteins; lipoprotein(a); atherosclerosis; gene; diabetes mellitus; interleukin; transcription; リポ蛋白; コレステロール; リポ蛋白(a)

Lipoprotein (a) (Lp (a) ) is known to be a strong risk factor for atherosclerotic diseases. However, the basic study for Lp (a) is behind because it is present only in man and monkeys so that suitable model has been lacking. In this study, we performed the clinical studies for hyperlipoproteinemia (a) observed in the patients with diabetes mellitus and chronic renal diseases, and analyzed the production and transcription of apolipoprotein (a) as basic studies using cynomolgus monkeys as animal model and HepG2 transfected with control region of genomic DNA of apolipoprotein as in vitro model. In patients with diabetes mellitus, serum level of Lp (a) is higher than in health subject. The serum level is correlated with the numbers of affected diabetic microangiopathic complications and with the level of HbAlc. The daily excretion of urinary C-peptide residue is incersely correlated with serum Lp (a) level, which suggests the decreased effect of insulin in diabetes is involved in the increase of Lp (a) level. In primary culture of monkey hepatocytes and transformed HepG2 cells, insulin decreased apo (a) promoter activity dose dependently in the range between 10pM and 1 microM.Increment of apo (a) promoter activity was independent from the increase of osmotic pressure and dose dependent. In the patients with chronic dialysis, both of the level of serum Lp (a) and serum IL-6 werehigher than healthy subjects, and positively correlated each other. IL-6 was found to increase the production of Lp (a) DNA transcription in the study with primary culture of monkey hepatocytes and transformed HepG2 cells. It was suggested that IL-6 is involved in the elevated level of serum Lp (a) in the patient with chronic dialysis and inflammatory diseases. It was found that TGF-betal and TNF-alpha decrease apo (a) promoter activities.

脂蛋白（a）（Lp（a））是动脉粥样硬化性疾病的重要危险因子。然而，由于Lp（a）仅存在于人和猴中，缺乏合适的模型，因此对Lp（a）的基础研究相对滞后。本研究以食蟹猴为动物模型，以转染载脂蛋白基因组DNA控制区的HepG 2为体外模型，对糖尿病和慢性肾病患者中观察到的高脂蛋白血症（a）进行了临床研究，并分析了载脂蛋白（a）的产生和转录作为基础研究。糖尿病患者血清Lp（a）水平高于健康人。血清水平与受影响的糖尿病微血管病变并发症的数量和HbAlc水平相关。尿C肽残留量与血清Lp（a）水平呈显著正相关，提示糖尿病胰岛素作用降低与Lp（a）水平升高有关。在原代培养的猴肝细胞和转化的HepG 2细胞中，在10 pM和1 μ M范围内，胰岛素剂量依赖性地降低apo（a）启动子活性。慢性透析患者血清Lp（a）和IL-6水平均高于健康人，且两者呈正相关。在原代培养的猴肝细胞和转化的HepG 2细胞的研究中发现IL-6增加Lp（a）DNA转录的产生。提示IL-6与慢性透析及炎症性疾病患者血清Lp（a）水平升高有关。发现TGF-β 1和TNF-α降低apo（a）启动子活性。

项目成果

松島 照彦: "カニクイザルを用いたリポ蛋白(a)代謝の研究" 長寿科学統合研究. 1. 206-209 (1994)

Teruhiko Matsushima：“利用食蟹猴进行脂蛋白（a）代谢的研究”长寿科学综合研究。1. 206-209（1994）。

松島照彦: "カニクイザルを用いたリポ蛋白(a)代謝の研究" 長寿科学総合研究. 1. 85-90 (1995)

Teruhiko Matsushima：“利用食蟹猴进行脂蛋白（a）代谢的研究”长寿科学综合研究。1. 85-90（1995）。