73 Citations (Scopus)

Abstract

Autosomal recessive hypercholesterolemia (ARH) is a genetic form of hypercholesterolemia that clinically resembles familial hypercholesterolemia (FH). As in FH, the rate of clearance of circulating low density lipoprotein (LDL) by the LDL receptor (LDLR) in the liver is markedly reduced in ARH. Unlike FH, LDL uptake in cultured fibroblasts from ARH patients is normal or only slightly impaired. The gene defective in ARH encodes a putative adaptor protein that has been implicated in linking the LDLR to the endocytic machinery. To determine the role of ARH in the liver, ARH-deficient mice were developed. Plasma levels of LDL-cholesterol were elevated in the chow-fed Arh-/- mice (83 ± 8 mg/dl versus 68 ± 8 mg/dl) but were lower than those of mice expressing no LDLR (Ldlr-/-) (197 ± 8 mg/dl). Cholesterol feeding elevated plasma cholesterol levels in both strains. The fractional clearance rate of radiolabeled LDL was reduced to similar levels in the Arh-/- and Ldlr-/- mice, whereas the rate of removal of α2-macroglobulin by the LDLR-related protein, which also interacts with ARH, was unchanged. Immunolocalization studies revealed that a much greater proportion of immunodetectable LDLR, but not LDLR-related protein, was present on the sinusoidal surface of hepatocytes in the Arh-/- mice. Taken together, these results are consistent with ARH playing a critical and specific role in LDLR endocytosis in the liver.

Original languageEnglish (US)
Pages (from-to)29024-29030
Number of pages7
JournalJournal of Biological Chemistry
Volume278
Issue number31
DOIs
StatePublished - Aug 1 2003

Fingerprint

LDL Receptors
Endocytosis
Sorting
LDL Lipoproteins
Low Density Lipoprotein Receptor-Related Protein-1
Liver
Hyperlipoproteinemia Type II
Cholesterol
Plasmas
Hypercholesterolemia
Macroglobulins
Fibroblasts
Low Density Lipoprotein Receptor-Related Protein-2
LDL Cholesterol
Machinery
Genes
Autosomal Recessive Hypercholesterolemia
Hepatocytes
Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

@article{8a41051d7f334a0e998ee214c521ef39,
title = "Normal sorting but defective endocytosis of the low density lipoprotein receptor in mice with autosomal recessive hypercholesterolemia",
abstract = "Autosomal recessive hypercholesterolemia (ARH) is a genetic form of hypercholesterolemia that clinically resembles familial hypercholesterolemia (FH). As in FH, the rate of clearance of circulating low density lipoprotein (LDL) by the LDL receptor (LDLR) in the liver is markedly reduced in ARH. Unlike FH, LDL uptake in cultured fibroblasts from ARH patients is normal or only slightly impaired. The gene defective in ARH encodes a putative adaptor protein that has been implicated in linking the LDLR to the endocytic machinery. To determine the role of ARH in the liver, ARH-deficient mice were developed. Plasma levels of LDL-cholesterol were elevated in the chow-fed Arh-/- mice (83 ± 8 mg/dl versus 68 ± 8 mg/dl) but were lower than those of mice expressing no LDLR (Ldlr-/-) (197 ± 8 mg/dl). Cholesterol feeding elevated plasma cholesterol levels in both strains. The fractional clearance rate of radiolabeled LDL was reduced to similar levels in the Arh-/- and Ldlr-/- mice, whereas the rate of removal of α2-macroglobulin by the LDLR-related protein, which also interacts with ARH, was unchanged. Immunolocalization studies revealed that a much greater proportion of immunodetectable LDLR, but not LDLR-related protein, was present on the sinusoidal surface of hepatocytes in the Arh-/- mice. Taken together, these results are consistent with ARH playing a critical and specific role in LDLR endocytosis in the liver.",
author = "Christopher Jones and Hammer, {Robert E} and Li, {Wei Ping} and Cohen, {Jonathan C} and Hobbs, {Helen H} and Joachim Herz",
year = "2003",
month = "8",
day = "1",
doi = "10.1074/jbc.M304855200",
language = "English (US)",
volume = "278",
pages = "29024--29030",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "31",

}

TY - JOUR

T1 - Normal sorting but defective endocytosis of the low density lipoprotein receptor in mice with autosomal recessive hypercholesterolemia

AU - Jones, Christopher

AU - Hammer, Robert E

AU - Li, Wei Ping

AU - Cohen, Jonathan C

AU - Hobbs, Helen H

AU - Herz, Joachim

PY - 2003/8/1

Y1 - 2003/8/1

N2 - Autosomal recessive hypercholesterolemia (ARH) is a genetic form of hypercholesterolemia that clinically resembles familial hypercholesterolemia (FH). As in FH, the rate of clearance of circulating low density lipoprotein (LDL) by the LDL receptor (LDLR) in the liver is markedly reduced in ARH. Unlike FH, LDL uptake in cultured fibroblasts from ARH patients is normal or only slightly impaired. The gene defective in ARH encodes a putative adaptor protein that has been implicated in linking the LDLR to the endocytic machinery. To determine the role of ARH in the liver, ARH-deficient mice were developed. Plasma levels of LDL-cholesterol were elevated in the chow-fed Arh-/- mice (83 ± 8 mg/dl versus 68 ± 8 mg/dl) but were lower than those of mice expressing no LDLR (Ldlr-/-) (197 ± 8 mg/dl). Cholesterol feeding elevated plasma cholesterol levels in both strains. The fractional clearance rate of radiolabeled LDL was reduced to similar levels in the Arh-/- and Ldlr-/- mice, whereas the rate of removal of α2-macroglobulin by the LDLR-related protein, which also interacts with ARH, was unchanged. Immunolocalization studies revealed that a much greater proportion of immunodetectable LDLR, but not LDLR-related protein, was present on the sinusoidal surface of hepatocytes in the Arh-/- mice. Taken together, these results are consistent with ARH playing a critical and specific role in LDLR endocytosis in the liver.

AB - Autosomal recessive hypercholesterolemia (ARH) is a genetic form of hypercholesterolemia that clinically resembles familial hypercholesterolemia (FH). As in FH, the rate of clearance of circulating low density lipoprotein (LDL) by the LDL receptor (LDLR) in the liver is markedly reduced in ARH. Unlike FH, LDL uptake in cultured fibroblasts from ARH patients is normal or only slightly impaired. The gene defective in ARH encodes a putative adaptor protein that has been implicated in linking the LDLR to the endocytic machinery. To determine the role of ARH in the liver, ARH-deficient mice were developed. Plasma levels of LDL-cholesterol were elevated in the chow-fed Arh-/- mice (83 ± 8 mg/dl versus 68 ± 8 mg/dl) but were lower than those of mice expressing no LDLR (Ldlr-/-) (197 ± 8 mg/dl). Cholesterol feeding elevated plasma cholesterol levels in both strains. The fractional clearance rate of radiolabeled LDL was reduced to similar levels in the Arh-/- and Ldlr-/- mice, whereas the rate of removal of α2-macroglobulin by the LDLR-related protein, which also interacts with ARH, was unchanged. Immunolocalization studies revealed that a much greater proportion of immunodetectable LDLR, but not LDLR-related protein, was present on the sinusoidal surface of hepatocytes in the Arh-/- mice. Taken together, these results are consistent with ARH playing a critical and specific role in LDLR endocytosis in the liver.

UR - http://www.scopus.com/inward/record.url?scp=0042206621&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0042206621&partnerID=8YFLogxK

U2 - 10.1074/jbc.M304855200

DO - 10.1074/jbc.M304855200

M3 - Article

C2 - 12746448

AN - SCOPUS:0042206621

VL - 278

SP - 29024

EP - 29030

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 31

ER -