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素。然而，对Lp(A)的基础研究相对滞后，因为Lp(A)只存在于人和猴子中，因此一直缺乏合适的模型。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HepG2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，并对载脂蛋白(A)的产生和转录进行了分析。糖尿病患者血清Lp(A)水平高于正常人。血清水平与糖尿病微血管病变的发生率及糖化血红蛋白水平呈正相关。每日尿C肽残留量与血清Lp(A)水平呈正相关，提示糖尿病患者胰岛素水平降低可能与Lp(A)水平升高有关。在原代培养的猴肝细胞和转化的HepG2细胞中，胰岛素在10~1微米范围内呈剂量依赖性地降低载脂蛋白(A)启动子活性。慢性透析患者血清Lp(A)和IL-6水平均高于正常对照组，且呈正相关。在原代培养猴肝细胞和转化的HepG2细胞的研究中，发现IL-6能促进Lp(A)DNA转录的产生。提示IL-6参与了慢性透析和炎症性疾病患者血清Lp(A)水平的升高。结果发现，转化生长因子-β1和肿瘤坏死因子-α降低载脂蛋白(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.