Dietary and hypothyroid hypercholesterolemia induces hepatic apolipoprotein E expression in the rat: direct role of cholesterol

Apolipoprotein E (apo E) exerts a protective effect against atherosclerosis , related to its role in intracellular cholesterol removal and remnants cle arance. In this study we investigated the effect of dietary and hypothyroid hypercholesterolemia, induced respectively by a high cholesterol diet and by propylthiouracil, on hepatic apo E expression in Wistar male rats. The N orthern and Western blot analysis of hepatic mRNA and protein levels showed a 2-3-fold increase of apo E in hypercholesterolemic rats compared to cont rols. The incubation of FAO rat hepatoma cells with 25-OH cholesterol and m evalonate led to a three-fold increase of apo E mRNA, demonstrating a direc t role of cholesterol on apo E expression. This effect was completely aboli shed by elevating intracellular cAMP levels with forskolin. Immunoblot and immunofluorescence analysis revealed that 25-OH cholesterol/mevalonate stro ngly increased also apo E protein synthesis and secretion in FAO cells. Our data demonstrate that hypercholesterolemia, apart of the cause (diet or hy pothyroidism) induces liver apo E expression in the rat and that this effec t can be directly related, via cAMP, to cholesterol. (C) 1999 Federation of European Biochemical Societies.