title: Response of 3-hydroxy-3-methylglutaryl CoA reductase to l-triiodothyronine in cultured fibroblasts from FH homozygotes.
abstract: The effect of l-triiodothyronine on 3-hydroxy-3-methylglutaryl CoA (HMG CoA) reductase activity was measured in cultured skin fibroblasts from patients with homozygous familial hypercholesterolemia (FH). The tested strains were obtained from 13 receptor-negative and 6 receptor-defective type homozygotes and 3 heterozygotes. Eleven out of 19 strains of cultured fibroblasts from FH homozygotes demonstrated high levels of the HMG CoA reductase activity when l-triiodothyronine was present in the culture medium. All the 11 strains that responded to l-triiodothyronine were the receptor-negative type in which the binding of LDL on the cell surface was completely lacking. Two receptor-negative type strains showed no response to the addition of l-triiodothyronine. In these strains, partially active receptors were synthesized and rapidly degraded. The effect of l-triiodothyronine on HMG CoA reductase was abolished by cycloheximide, and not by actinomycin D. Furthermore, the effect was abolished by the pre-loading of the cells with free cholesterol. The results indicate that the effect of l-triiodothyronine on HMG CoA reductase activity was a post-transcriptional event, required de novo protein synthesis, and was successful only when cholesterol was depleted from the cells. The difference in the responsiveness of HMG CoA reductase activity to l-triiodothyronine treatment can be utilized to judge the state of impairment of LDL-receptors in the FH homozygote from the viewpoint of ability to incorporate cholesterol into the cells.
authors.affiliation: Department of Etiology and Pathophysiology, National Cardiovascular Center Research Institute, Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Harada-Shiba
authors.forename: S
authors.initials: S
authors.lastname: Tajima
authors.forename: A
authors.initials: A
authors.lastname: Yamamoto
mesh_terms: D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006720:Homozygote; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D006938:Hyperlipoproteinemia Type II / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000378:metabolism; D012867:Skin / Q000166:cytology; D014284:Triiodothyronine / Q000494:pharmacology*
chemical_list: D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D014284:Triiodothyronine; D003609:Dactinomycin; D003513:Cycloheximide; D006903:Hydroxymethylglutaryl CoA Reductases