Xia Hui, Redman Colvin M
Lindsley F Kimball Research Institute of the New York Blood Center, New York, NY 10021, USA.
Thromb Haemost. 2003 Jul;90(1):43-51.
Elevated levels of both fibrinogen and cholesterol are risk factors in coronary artery disease. Previously we reported a metabolic link between fibrinogen and lipid metabolism in that HepG2 cells that were programmed by transfection of Bbeta-fibrinogen cDNA to overexpress fibrinogen exhibited increased synthesis of cholesterol and increased secretion of apolipoprotein B. In this study we demonstrate that oxysterols, which participate in maintaining cholesterol homeostasis, also down regulate fibrinogen expression. Treatment of HepG2 cells with 25-hydroxycholesterol lowered fibrinogen Aalpha, Bbeta and gamma mRNA levels and inhibited fibrinogen synthesis and secretion but had no effect on alpha1 -antitrypsin which, like fibrinogen, is an acute-phase protein. The inhibition of fibrinogen synthesis by oxysterols was maintained in interleukin-6 treated cells. Other oxysterols, that inhibit cholesterol synthesis by a feedback mechanism, also diminished fibrinogen expression in HepG2, rat H-4-II-E hepatoma cells and in primary human hepatocytes. Overexpression of SREBP-1 and SREBP-2 by transfection of HepG2 cells, or treatment with a synthetic LXRalpha agonist, which affect cholesterol metabolism, did not affect fibrinogen expression. We conclude that fibrinogen and cholesterol may share a novel common regulatory pathway.
纤维蛋白原和胆固醇水平升高均为冠状动脉疾病的危险因素。此前我们报道了纤维蛋白原与脂质代谢之间的代谢联系，即通过转染β-纤维蛋白原cDNA使HepG2细胞过表达纤维蛋白原后，其胆固醇合成增加，载脂蛋白B分泌增多。在本研究中，我们证明参与维持胆固醇稳态的氧化甾醇也会下调纤维蛋白原的表达。用25-羟基胆固醇处理HepG2细胞可降低纤维蛋白原α、β和γ mRNA水平，并抑制纤维蛋白原的合成与分泌，但对α1-抗胰蛋白酶无影响，α1-抗胰蛋白酶与纤维蛋白原一样，是一种急性期蛋白。在白细胞介素-6处理的细胞中，氧化甾醇对纤维蛋白原合成的抑制作用依然存在。其他通过反馈机制抑制胆固醇合成的氧化甾醇，也会使HepG2细胞、大鼠H-4-II-E肝癌细胞和原代人肝细胞中的纤维蛋白原表达减少。通过转染使HepG2细胞过表达固醇调节元件结合蛋白-1（SREBP-1）和固醇调节元件结合蛋白-2（SREBP-2），或用影响胆固醇代谢的合成肝X受体α（LXRα）激动剂处理，均不影响纤维蛋白原的表达。我们得出结论，纤维蛋白原和胆固醇可能共享一条新的共同调节途径。
