Autosomal recessive hypercholesterolemia (ARH) and homozygous familial hypercholesterolemia (FH): A phenotypic comparison

Pisciotta, Livia; Oliva, Claudio Priore; Pes, Giovanni Mario; Scala, Lilla Di; Bellocchio, Antonella; Fresa, Raffaele; Cantàfora, Alfredo; Arca, Marcello; Calandra, Sebastiano

doi:10.1016/j.atherosclerosis.2005.11.016

Cited by 90 publications

(52 citation statements)

References 25 publications

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“…5,6 The N-terminal domain of LDLRAP1 contains a phosphotyrosine-binding (PTB) domain, which binds to the internalization sequence (FDNPVY) in the cytoplasmic tail of the LDLR. 7 LDLRAP1 protein serves as an adaptor for LDLR endocytosis in the liver Received December 1, 2009; accepted November 28, 2011.…”

Section: Clinical Perspective On P 41mentioning

confidence: 99%

“…8 However, ARH differs from homozygous FH in the severity of the clinical phenotype and response to statins, the cause of which still remains unclear. 5 One of the possible mechanisms of great responsiveness to statins was elucidated by a metabolic study using LDLRAP1 knockout mice that showed preserved ability for LDLRdependent VLDL clearance. 9 However, few data exist regarding the metabolic basis of LDLRAP1 in clinical settings, especially, the metabolism of remnant lipoprotein fractions.…”

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confidence: 99%

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Altered Metabolism of Low-Density Lipoprotein and Very-Low-Density Lipoprotein Remnant in Autosomal Recessive Hypercholesterolemia

Tada

Kawashiri

Ikewaki

et al. 2012

Circ Cardiovasc Genet

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Background-Autosomal recessive hypercholesterolemia (ARH) exhibits different responsiveness to statins compared with that in homozygous familial hypercholesterolemia (FH). However, few data exist regarding lipoprotein metabolism of ARH. Therefore, we aimed to clarify lipoprotein metabolism, especially the remnant lipoprotein fractions of ARH before and after statin therapy. Methods and Results-We performed a lipoprotein kinetic study in an ARH patient and 7 normal control subjects, using stable isotope methodology (10 mg/kg of [ 2 H 3 ]-leucine). These studies were performed at baseline and after the 20 mg daily dose of atorvastatin. Tracer/tracee ratio of apolipoprotein B (apoB) was determined by gas chromatography/mass spectrometry and fractional catabolic rates (FCR) were determined by multicompartmental modeling, including remnant lipoprotein fractions. FCR of low-density lipoprotein (LDL) apoB of ARH was significantly lower than those of control subjects (0.109 versus 0.450Ϯ0.122 1/day). In contrast, the direct removal of very-low-density lipoprotein remnant was significantly greater in ARH than those in control subjects (47.5 versus 2Ϯ2%). Interestingly, FCR of LDL apoB in ARH dramatically increased to 0.464 1/day, accompanying reduction of LDL cholesterol levels from 8.63 to 4.22 mmol/L after treatment with atorvastatin of 20 mg/d for 3 months.Conclusions-These results demonstrate that ARH exhibits decreased LDL clearance associated with decreased FCR of LDL apoB and increased clearance for very-low-density lipoprotein remnant. We suggest that increased clearance of remnant lipoprotein fractions could contribute to the great responsiveness to statins, providing new insights into the lipoprotein metabolism of ARH and the novel pharmacological target for LDLRAP1. (Circ Cardiovasc Genet. 2012;5:35-41.)Key Words: lipoproteins Ⅲ ARH Ⅲ genetics Ⅲ metabolism Ⅲ LDLRAP1 F amilial hypercholesterolemia (FH) is a common inherited disorder of plasma lipoprotein metabolism, characterized by an elevated level of low-density lipoprotein cholesterol (LDL-C), tendon xanthomas, and premature coronary artery disease. 1 Genetic causes of FH involve gene mutations such as LDL receptor (LDLR), apolipoprotein B-100 (apoB-100), and proprotein convertase subtilisin/kexin type 9 (PCSK9). 2 In contrast, there was a report of autosomal recessive inherited cases, who showed elevation of LDL-C, large xanthomas, and premature coronary artery disease typical of homozygous FH but in whom the fibroblasts had normal LDLR function. 3 Subsequently, Garcia et al 4 showed that this disorder was caused by a recessive form of null mutations in the LDLR adaptor protein 1 (LDLRAP1). Clinical Perspective on p 41Since then, evidence has been accumulating that it was not linked to mutations in the LDLR gene. 5,6 The N-terminal domain of LDLRAP1 contains a phosphotyrosine-binding (PTB) domain, which binds to the internalization sequence (FDNPVY) in the cytoplasmic tail of the LDLR. 7 LDLRAP1 protein serves as an adaptor for LDLR endocytosis in the live...

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Section: Clinical Perspective On P 41mentioning

confidence: 99%

mentioning

confidence: 99%

Altered Metabolism of Low-Density Lipoprotein and Very-Low-Density Lipoprotein Remnant in Autosomal Recessive Hypercholesterolemia

Tada

Kawashiri

Ikewaki

et al. 2012

Circ Cardiovasc Genet

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“…Despite comparable reductions in the fractional catabolic rate (FCR) of LDL, the metabolic and clinical phenotype of ARH tends to be less severe than that of FH (1)(2)(3)(4)(12)(13)(14)(15)(16)(17)(18); plasma levels of LDL are lower and the onset of coronary artery disease is usually later in ARH subjects than in FH homozygotes. ARH patients also respond to lipid-lowering agents with a greater reduction in plasma levels of LDL than is typically observed in patients with homozygous FH.…”

Section: Introductionmentioning

confidence: 99%

Disruption of LDL but not VLDL clearance in autosomal recessive hypercholesterolemia

Jones¹,

Garuti²,

Michaely³

et al. 2007

J. Clin. Invest.

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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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“…Furthermore, the prevalence of CAD was or tended to be lower in ARH in the 21-40 (45% versus 86%) and 41-60 (78% versus 100%) age groups. Of note, heterozygous ARH carriers showed higher level of LDL-C (+17%) than non-carrier family members [8].…”

Section: Clinical Phenotype Of Patients With Arhmentioning

confidence: 91%

Autosomal Recessive Hypercholesterolemia: A Rare Cause of Familial Hypercholesterolemia

Kosmas¹

2017

BJSTR

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Autosomal recessive hypercholesterolemia (ARH) and homozygous familial hypercholesterolemia (FH): A phenotypic comparison

Cited by 90 publications

References 25 publications

Altered Metabolism of Low-Density Lipoprotein and Very-Low-Density Lipoprotein Remnant in Autosomal Recessive Hypercholesterolemia

Altered Metabolism of Low-Density Lipoprotein and Very-Low-Density Lipoprotein Remnant in Autosomal Recessive Hypercholesterolemia

Disruption of LDL but not VLDL clearance in autosomal recessive hypercholesterolemia

Autosomal Recessive Hypercholesterolemia: A Rare Cause of Familial Hypercholesterolemia

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