UP-REGULATION OF LOW-DENSITY-LIPOPROTEIN RECEPTOR BY GEMFIBROZIL, A HYPOLIPIDEMIC AGENT, IN HUMAN HEPATOMA-CELLS THROUGH STABILIZATION OF MESSENGER-RNA TRANSCRIPTS

Gemfibrozil reduces the plasmal levels of cholesterol and triglyceride in patients with hyperlipidemia by a mechanism that is not well under stood. The present study evaluated the effect of gemfibrozil on the LD L receptor in human hepatoma cells compared with that of pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Expos ure to gemfibrozil, 40 mu mol/L, for 3 days increased the binding of I -125-LDL to the surface of three lines of human hepatoma cell, HepG2, HuH7, and HLE by 1.5- to 20-fold. Similar findings were observed with pravastatin. Scatchard analysis with I-125-LDL indicated an increased number of LDL receptors on the cell surface of HepG2 cells when treate d with gemfibrozil and pravastatin. However, the gemfibrozil-treated c ells exhibited no increase in the binding of I-125-epidermal growth fa ctor (EGF). Gemfibrozil increased the levels of LDL receptor mRNA and protein in HepG2 cells. The increase in LDL receptor activity induced by pravastatin was abolished by concomitant administration of mevaloni c acid, 770 mu mol/L. This effect was not seen with gemfibrozil, sugge sting the mechanism differs for the two lipid-lowering drugs. To deter mine whether this increase in mRNA was due to transcriptional activati on, we prepared HepG2 cells transfected with an LDL receptor promoter- reporter construct that contained a sterol regulatory element. The exp ression of LDL receptor regulated by the sterol regulatory element was increased by pravastatin, but not by gemfibrozil. We evaluated the st ability of the mRNA in the presence of actinomycin D to explain the in crease in the LDL receptor mRNA. Gemfibrozil prolonged the half-life o f the mRNA for LDL receptor but not that for the EGF receptor. Stabili zation of the LDL receptor mRNA is suggested to be the novel mode of a ction of gemfibrozil.