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Cell Culture Conditions Determine Apolipoprotein CIII Secretion and Regulation by Fibrates in Human Hepatoma HepG2 Cells

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)α 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 PPARγ-specific ligand, the antidiabetic thiazolidinedione, BRL-49653 and a PPARα ligand Wy-14643 showed a marked decrease of apo CIII secretion and gene expression after activation of PPARα but not PPARγ. In conclusion, fibrates down-regulate apo CIII gene expression in human HepG2 cells, most likely via PPARα but not via PPARγ. However, these effects are only observed in HepG2 cells cultured under appropriate conditions.