Response of 3-hydroxy-3-methylglutaryl CoA reductase to l-triiodothyronine in cultured fibroblasts from FH homozygotes Original Research Article

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 receptornegative 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.