Liver transplantation to provide low-density-lipoprotein receptors and lower plasma cholesterol in a child with homozygous familial hypercholesterolemia
DW Bilheimer, JL Goldstein, SM Grundy, TE Starzl, and MS Brown
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.
This article has been cited by other articles:
Bradshaw, G., Gutierrez, A., Miyake, J. H., Davis, K. R., Li, A. C., Glass, C. K., Curtiss, L. K., Davis, R. A.
(2005). Facilitated replacement of Kupffer cells expressing a paraoxonase-1 transgene is essential for ameliorating atherosclerosis in mice. Proc. Natl. Acad. Sci. USA
102: 11029-11034
[Abstract][Full Text]
Ness, G. C., Gertz, K. R.
(2004). Hepatic HMG-CoA Reductase Expression and Resistance to Dietary Cholesterol. Exp. Biol. Med.
229: 412-416
[Abstract][Full Text]
Liao, W., Hui, T. Y., Young, S. G., Davis, R. A.
(2003). Blocking microsomal triglyceride transfer protein interferes with apoB secretion without causing retention or stress in the ER. J. Lipid Res.
44: 978-985
[Abstract][Full Text]
Ness, G. C., Chambers, C. M.
(2000). Feedback and Hormonal Regulation of Hepatic 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase: The Concept of Cholesterol Buffering Capacity. Exp. Biol. Med.
224: 8-19
[Abstract][Full Text]
Milner, J. A., Allison, R. G.
(1999). The Role of Dietary Fat in Child Nutrition and Development: Summary of an ASNS Workshop. J. Nutr.
129: 2094-2105
[Full Text]
Wilson, G. M., Vasa, M. Z., Deeley, R. G.
(1998). Stabilization and cytoskeletal-association of LDL receptor mRNA are mediated by distinct domains in its 3' untranslated region. J. Lipid Res.
39: 1025-1032
[Abstract][Full Text]
Post, S. M., de Wit, E. C. M., Princen., H. M. G.
(1997). Cafestol, the Cholesterol-Raising Factor in Boiled Coffee, Suppresses Bile Acid Synthesis by Downregulation of Cholesterol 7{alpha}-Hydroxylase and Sterol 27-Hydroxylase in Rat Hepatocytes. Arterioscler. Thromb. Vasc. Bio.
17: 3064-3070
[Abstract][Full Text]
Starzl, T. E., Demetris, A. J., Trucco, M., Ricordi, C., Ildstad, S., Terasaki, P. I., Murase, N., Kendall, R. S., Kocova, M., Rudert, W. A., Zeevi, A., Van Thiel, D.
(1993). Chimerism after Liver Transplantation for Type IV Glycogen Storage Disease and Type 1 Gaucher's Disease. NEJM
328: 745-749
[Abstract][Full Text]
Gherardi, E., Thomas, K., Le Cras, T. D., Fitzsimmons, C., Moorby, C. D., Bowyer, D. E.
(1992). Growth requirements and expression of LDL receptor and HMG-CoA reductase in Hep G2 hepatoblastoma cells cultured in a chemically defined medium. J. Cell Sci.
103: 531-539
[Abstract]
Chowdhury, JR, Grossman, M, Gupta, S, Chowdhury, N., Baker, J. Jr, Wilson, J.
(1991). Long-term improvement of hypercholesterolemia after ex vivo gene therapy in LDLR-deficient rabbits. Science
254: 1802-1805
[Abstract]
Brown, M., Goldstein, J.
(1986). A receptor-mediated pathway for cholesterol homeostasis. Science
232: 34-47
Previous
