Disruption of Autosomal Recessive Hypercholesterolemia Gene Shows Different Phenotype In Vitro and In Vivo
- 29 October 2004
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation Research
- Vol. 95 (9), 945-952
- https://doi.org/10.1161/01.res.0000146946.78540.46
Abstract
We previously characterized the patients with autosomal recessive hypercholesterolemia (ARH) as having severe hypercholesterolemia and retarded plasma low-density lipoprotein (LDL) clearance despite normal LDL receptor (LDLR) function in their cultured fibroblasts, and we identified a mutation in the ARH locus in these patients. ARH protein is an adaptor protein of the LDL and reportedly modulates its internalization. We developed ARH knockout mice (ARH−/−) to study the function of this protein. Plasma total cholesterol level was higher in ARH−/− mice than that in wild-type mice (ARH+/+), being attributed to a 6-fold increase of LDL, whereas plasma lipoprotein was normal in the heterozygotes (ARH+/−). Clearance of 125I-LDL from plasma was retarded in ARH−/− mice, as much as that found in LDLR−/− mice. Fluorescence activity of the intravenously injected 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI)-LDL was recovered in the cytosol of the hepatocytes of ARH+/+ mice, but not in those of ARH−/− or LDLR−/− mice. Also, less radioactivity was recovered in the liver of ARH−/− or LDLR−/− mice when [3H]cholesteryl oleyl ether (CE)-labeled LDL was injected. In contrast, uptakes of [3H]CE-labeled LDL, 125I-LDL, and DiI-LDL were all normal or slightly subnormal when the ARH−/− hepatocytes were cultured. We thus concluded that the function of the hepatic LDLR is impaired in the ARH−/− mice in vivo, despite its normal function in vitro. These findings were consistent with the observations with the ARH homozygous patients and suggested that certain cellular environmental factors modulate the requirement of ARH for the LDLR function.Keywords
This publication has 18 references indexed in Scilit:
- The Modular Adaptor Protein ARH Is Required for Low Density Lipoprotein (LDL) Binding and Internalization but Not for LDL Receptor Clustering in Coated PitsOnline Journal of Public Health Informatics, 2004
- Normal Sorting but Defective Endocytosis of the Low Density Lipoprotein Receptor in Mice with Autosomal Recessive HypercholesterolemiaOnline Journal of Public Health Informatics, 2003
- ARH Is a Modular Adaptor Protein That Interacts with the LDL Receptor, Clathrin, and AP-2Online Journal of Public Health Informatics, 2002
- Autosomal Recessive Hypercholesterolemia Caused by Mutations in a Putative LDL Receptor Adaptor ProteinScience, 2001
- Characterization of a novel cellular defect in patients with phenotypic homozygous familial hypercholesterolemiaJCI Insight, 1999
- Acquisition of Secretion of Transforming Growth Factor-β1 Leads to Autonomous Suppression of Scavenger Receptor Activity in a Monocyte-Macrophage Cell Line, THP-1Online Journal of Public Health Informatics, 1998
- Severe hypercholesterolaemia: unusual inheritance in an Italian pedigreeEuropean Journal of Clinical Investigation, 1995
- Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery.JCI Insight, 1993
- Experiences with the Homozygous Cases of Familial HypercholesterolemiaAnnals of Nutrition and Metabolism, 1973
- The metabolism of very low density lipoprotein proteins I. Preliminary in vitro and in vivo observationsBiochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, 1972