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.
Shakhov
Y
Y
National Research Center for Preventive Medicine, Moscow, Russia.
Petrichenko
I
I
Fuki
I
I
D000328:Adult; D001665:Binding Sites; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002784:Cholesterol / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000378:metabolism* / Q000473:pathology; D008297:Male; D011965:Receptors, Glucocorticoid / Q000187:drug effects; D012680:Sensitivity and Specificity; D012867:Skin / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014316:Tritium
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D014316:Tritium; D003907:Dexamethasone; D002784:Cholesterol