51 Citations (Scopus)

Abstract

Genetic defects in LDL clearance result in severe hypercholesterolemia and premature atherosclerosis. Mutations in the LDL receptor (LDLR) cause familial hypercholesterolemia (FH), the most severe form of genetic hypercholesterolemia. A phenocopy of FH, autosomal recessive hypercholesterolemia (ARH), is due to mutations in an adaptor protein involved in LDLR internalization. Despite comparable reductions in LDL clearance rates, plasma LDL levels are substantially lower in ARH than in FH. To determine the metabolic basis for this difference, we examined the synthesis and catabolism of VLDL in murine models of FH (Ldlr-/-) and ARH (Arh-/-). The hyperlipidemic response to a high-sucrose diet was greatly attenuated in Arh-/- mice compared with Ldlr-/- mice despite similar rates of VLDL secretion. The rate of VLDL clearance was significantly higher in Arh-/- mice than in Ldlr-/- mice, suggesting that LDLR-dependent uptake of VLDL is maintained in the absence of ARH. Consistent with these findings, hepatocytes from Arh-/- mice (but not Ldlr-/- mice) internalized β-migrating VLDL (β-VLDL). These results demonstrate that ARH is not required for LDLR-dependent uptake of VLDL by the liver. The preservation of VLDL remnant clearance attenuates the phenotype of ARH and likely contributes to greater responsiveness to statins in ARH compared with FH.

Original languageEnglish (US)
Pages (from-to)165-174
Number of pages10
JournalJournal of Clinical Investigation
Volume117
Issue number1
DOIs
StatePublished - Jan 4 2007

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Hyperlipoproteinemia Type II
LDL Receptors
Hypercholesterolemia
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Mutation
oxidized low density lipoprotein
Autosomal Recessive Hypercholesterolemia
Sucrose
Hepatocytes
Atherosclerosis
Diet
Phenotype
Liver
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Disruption of LDL but not VLDL clearance in autosomal recessive hypercholesterolemia. / Jones, Christopher; Garuti, Rita; Michaely, Peter; Li, Wei Ping; Maeda, Nobuyo; Cohen, Jonathan C.; Herz, Joachim; Hobbs, Helen H.

In: Journal of Clinical Investigation, Vol. 117, No. 1, 04.01.2007, p. 165-174.

Research output: Contribution to journalArticle

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abstract = "Genetic defects in LDL clearance result in severe hypercholesterolemia and premature atherosclerosis. Mutations in the LDL receptor (LDLR) cause familial hypercholesterolemia (FH), the most severe form of genetic hypercholesterolemia. A phenocopy of FH, autosomal recessive hypercholesterolemia (ARH), is due to mutations in an adaptor protein involved in LDLR internalization. Despite comparable reductions in LDL clearance rates, plasma LDL levels are substantially lower in ARH than in FH. To determine the metabolic basis for this difference, we examined the synthesis and catabolism of VLDL in murine models of FH (Ldlr-/-) and ARH (Arh-/-). The hyperlipidemic response to a high-sucrose diet was greatly attenuated in Arh-/- mice compared with Ldlr-/- mice despite similar rates of VLDL secretion. The rate of VLDL clearance was significantly higher in Arh-/- mice than in Ldlr-/- mice, suggesting that LDLR-dependent uptake of VLDL is maintained in the absence of ARH. Consistent with these findings, hepatocytes from Arh-/- mice (but not Ldlr-/- mice) internalized β-migrating VLDL (β-VLDL). These results demonstrate that ARH is not required for LDLR-dependent uptake of VLDL by the liver. The preservation of VLDL remnant clearance attenuates the phenotype of ARH and likely contributes to greater responsiveness to statins in ARH compared with FH.",
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