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

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，转染载脂蛋白基因组DNA控制区的HepG 2为体外模型，对糖尿病和慢性肾脏疾病患者的高脂蛋白血症（a）进行了临床研究，并分析了载脂蛋白（a）的产生和转录。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。在猴肝细胞和转化HepG 2细胞的原代培养中，胰岛素在10 pM至1 μ M范围内呈剂量依赖性降低apo（a）启动子活性。apo（a）启动子活性的增加与渗透压的增加无关，且具有剂量依赖性。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。

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.