Characterization of a New Form of Inherited Hypercholesterolemia

Author:

Zuliani G.1,Arca M.1,Signore A.1,Bader G.1,Fazio S.1,Chianelli M.1,Bellosta S.1,Campagna F.1,Montali A.1,Maioli M.1,Pacifico A.1,Ricci G.1,Fellin R.1

Affiliation:

1. From the Department of Internal Medicine, University of Ferrara, Ferrara (G.Z., G.B., R.F.), and the Institute of Terapia Medica Sistematica (M.A., F.C., A.M., G.R.) and Service of Nuclear Medicine (A.S., M.C.), Department of Internal Medicine II, University of Rome “La Sapienza,” Rome, Italy; Vanderbilt University Medical School, Nashville, Tenn (S.F.); and the Institute of Pharmacological Science, University of Milan, Milan (S.B.), and the Department of Internal Medicine, University of Sassari,...

Abstract

Abstract —We previously described a Sardinian family in which the probands had a severe form of hypercholesterolemia, suggestive of familial hypercholesterolemia (FH). However, low density lipoprotein (LDL) receptor activity in fibroblasts from these subjects and LDL binding ability were normal. The characteristics of the pedigree were consistent with an autosomal recessive trait. Sitosterolemia and pseudohomozygous hyperlipidemia were ruled out. A second Sardinian kindred with similar characteristics was identified. Probands showed severe hypercholesterolemia, whereas their parents and grandparents were normolipidemic. FH, familial defective apoprotein (apo) B, sitosterolemia, and cholesteryl ester storage disease were excluded by in vitro studies. We addressed the metabolic basis of this inherited disorder by studying the in vivo metabolism of LDL in 3 probands from these 2 families. 125 I-LDL turnover studies disclosed a marked reduction in the fractional catabolic rate (0.19±0.01 versus 0.36±0.03 pools per day, respectively; P <0.001) and a significant increase in the production rate [20.7±4.4 versus 14.0±2.4 mg · kg −1 · d −1 , respectively; P <0.01] of LDL apoB in the probands compared with normolipidemic controls. We then studied the in vivo biodistribution and tissue uptake of 99m technetium-labeled LDL in the probands and compared them with those in normal controls and 1 FH homozygote. The probands showed a significant reduction in hepatic LDL uptake, similar to that observed in the FH homozygote. A reduced uptake of LDL by the kidney and spleen was also observed in all patients. Our findings suggest that this recessive form of hypercholesterolemia is due to a marked reduction of in vivo LDL catabolism. This appears to be caused by a selective reduction in hepatic LDL uptake. We propose that in this new lipid disorder, a recessive defect causes a selective impairment of LDL receptor function in the liver.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

Reference37 articles.

1. THE LDL RECEPTOR LOCUS IN FAMILIAL HYPERCHOLESTEROLEMIA: Mutational Analysis of a Membrane Protein

2. Goldstein JL Brown MS. Familial hypercholesterolemia. In: Scriver CR Beaudet AI Sly WS Valle D eds. The Metabolic Basis of Inherited Diseases. New York NY: McGraw-Hill; 1990:1215–1250.

3. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100.

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