Liver transplantation to provide low-density-lipoprotein receptors and lower plasma cholesterol in a child with homozygous familial hypercholesterolemia

Abstract

A six-year-old girl with severe hypercholesterolemia and atherosclerosis had two defective genes at the low-density-lipoprotein (LDL) receptor locus, as determined by biochemical studies of cultured fibroblasts. One gene, inherited from the mother, produced no LDL receptors; the other gene, inherited from the father, produced a receptor precursor that was not transported to the cell surface and was unable to bind LDL. The patient degraded intravenously administered 125I-LDL at an extremely low rate, indicating that her high plasma LDL-cholesterol level was caused by defective receptor-mediated removal of LDL from plasma. After transplantation of a liver and a heart from a normal donor, the patient's plasma LDL-cholesterol level declined by 81 per cent, from 988 to 184 mg per deciliter. The fractional catabolic rate for intravenously administered 125I-LDL, a measure of functional LDL receptors in vivo, increased by 2.5-fold. Thus, the transplanted liver, with its normal complement of LDL receptors, was able to remove LDL cholesterol from plasma at a nearly normal rate. We conclude that a genetically determined deficiency of LDL receptors can be largely reversed by liver transplantation. These data underscore the importance of hepatic LDL receptors in controlling the plasma level of LDL cholesterol in human beings.

Figure 1

Kinetics of Processing of LDL Receptors in Fibroblasts from a Normal Subject and Patient FH 728. Cells were incubated in methionine-free medium containing [³⁵S]methionine for one hour. The medium was then switched to complete medium containing unlabeled methionine for either 15 minutes (A, C, E, and G) or two hours (B, D, F, and H), after which the cells were dissolved in detergents and LDL receptors were immunoprecipitated with monoclonal antireceptor IgG-C7 (A to D). Control precipitations were performed with control monoclonal IgG-2001 (E to H). The immunoprecipitates were subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis and fluorography. The positions of migration of the unprocessed precursor receptor (120,000 daltons) and the processed mature receptor (160,000 daltons) are indicated.

Figure 2

Electrophoresis of ³⁵S-Labeled LDL Receptors from Patient FH 728 and Her Heterozygous Parents. Fibroblasts from the indicated subject were incubated in methionine-free medium containing [³⁵S]methionine for two hours (pulse). The medium was then switched to complete medium for two hours (chase), after which LDL receptors were immunoprecipitated and processed for sodium dodecyl sulfate polyacrylamide gel electrophoresis and fluorography. The positions of migration of the unprocessed precursor receptor (120,000 daltons) and the processed mature receptor (160,000 daltons) are indicated.

Figure 3

Plasma Decay Curves after Intravenous Injection of ¹²⁵I-LDL in the Patient before and after Liver–Heart Transplantation.