Clavey V, Copin C, Mariotte M C, Baugé E, Chinetti G, Fruchart J, Fruchart J C, Dallongeville J, Staels B
INSERM U325, Institut Pasteur de Lille et Faculté de Pharmacie, Université Lille 2, Lille, France.
Cell Physiol Biochem. 1999;9(3):139-49. doi: 10.1159/000016311.
Fibrates are widely used drugs which lower triglycerides and increase HDL concentrations in serum. Recent findings from our laboratory have shown that fibrates repress apolipoprotein (apo) CIII gene expression, an effect that explains partially the triglyceride-lowering activity of these drugs. The goal of the present study was to compare the effect of various fibrates on apo CIII gene expression in the human hepatoblastoma cell line HepG2. First, we demonstrate that the level of apo CIII secretion by HepG2 cells is controlled by serum factors whereas apo CIII mRNA levels are not and even increase under conditions when apo CIII secretion dramatically decreases. Twelve different fetal calf serum batches were tested during this study and apo CIII secretion in cell medium could only be detected with three of them. The effect of serum on apolipoprotein secretion was more pronounced for apo CIII whereas other apolipoproteins (apo E, apo B, apo AII and apo AI) were affected to a lesser extent. Under serum conditions allowing apo CIII secretion, treatment with the peroxisome-proliferator activated receptor (PPAR)alpha activators fenofibrate, gemfibrozil and Wy-14643 result in a marked lowering of apo CIII secretion and gene expression, this effect being most pronounced with Wy-14643. Comparison of the activity of a PPARgamma-specific ligand, the antidiabetic thiazolidinedione, BRL-49653 and a PPARalpha ligand Wy-14643 showed a marked decrease of apo CIII secretion and gene expression after activation of PPARalpha but not PPARgamma. In conclusion, fibrates down-regulate apo CIII gene expression in human HepG2 cells, most likely via PPARalpha but not via PPARgamma. However, these effects are only observed in HepG2 cells cultured under appropriate conditions.
贝特类药物是广泛使用的药物，可降低甘油三酯并提高血清中高密度脂蛋白（HDL）的浓度。我们实验室最近的研究结果表明，贝特类药物可抑制载脂蛋白（apo）CIII基因的表达，这一作用部分解释了这些药物降低甘油三酯的活性。本研究的目的是比较不同贝特类药物对人肝癌细胞系HepG2中apo CIII基因表达的影响。首先，我们证明HepG2细胞分泌apo CIII的水平受血清因子控制，而apo CIII mRNA水平不受血清因子控制，甚至在apo CIII分泌显著减少的情况下反而增加。在本研究中测试了12个不同批次的胎牛血清，仅在其中3个批次中检测到细胞培养基中有apo CIII分泌。血清对载脂蛋白分泌的影响对apo CIII更为明显，而其他载脂蛋白（apo E、apo B、apo AII和apo AI）受到的影响较小。在允许apo CIII分泌的血清条件下，用过氧化物酶体增殖物激活受体（PPAR）α激动剂非诺贝特、吉非贝齐和Wy-14643处理可导致apo CIII分泌和基因表达显著降低，其中Wy-14643的这种作用最为明显。比较PPARγ特异性配体、抗糖尿病噻唑烷二酮类药物BRL-49653和PPARα配体Wy-14643的活性，结果显示激活PPARα后apo CIII分泌和基因表达显著降低，而激活PPARγ后则无此现象。总之，贝特类药物在人HepG2细胞中下调apo CIII基因表达，最可能是通过PPARα而非PPARγ。然而，这些作用仅在适当条件下培养的HepG2细胞中观察到。
