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.
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U2 - 10.1074/jbc.M304855200
DO - 10.1074/jbc.M304855200
M3 - Article
C2 - 12746448
AN - SCOPUS:0042206621
SN - 0021-9258
VL - 278
SP - 29024
EP - 29030
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 31
ER -