Reduced sensitivity of cultured skin fibroblasts from familial hypercholesterolemic patients to glucocorticoids.

Cultured human skin fibroblasts, obtained from patients with homozygous familial hypercholesterolemia (FH), exhibited cholesterol synthesis that was 2.5-3-fold more intensive than in cells from healthy donors (normal cells). The study of the glucocorticoid [3H]-dexamethasone specific binding (glucocorticoid receptors, GcR) to the cells showed reduced number of binding sites (8 x 10(3) vs 120 x 10(3) binding sites/cell) and reduced Kd value (5.6 +/- 0.7 vs 10.1 +/- 2.1 nM) in FH-fibroblasts when compared with normal fibroblasts. The inhibition by 1 x 10(-8) and 1 x 10(-6) M dexamethasone of cholesterol synthesis was less marked in FH-cells (29.1 +/- 2.8 and 35.9 +/- 1.2%) as compared with normal cells (53.3 +/- 1.0% and 60.4 +/- 9.6, respectively). This findings indicate that the sensitivity of FH-fibroblasts to glucocorticoids is reduced. They also suggest that reduced number of GcR found in FH-fibroblasts reflects the cellular adaptation to cholesterol deficiency resulted from the absence of LDL-receptors.