Identification and characterization of novel loss of function mutations in ATP-binding cassette transporter A1 in patients with low plasma high-density lipoprotein cholesterol

Candini, C.; Schimmel, Alinda W.M.; Peter, Jorge; Bochem, Andrea E.; Holleboom, Adriaan G.; Vergeer, Menno; Dullaart, Robin; Dallinga‐Thie, Geesje M.; Hovingh, G. Kees; Khoo, K.L.; Fasano, Tommaso; Bocchi, Leonardo; Calandra, Sebastiano; Kuivenhoven, Jan Albert; Motazacker, Mohammad Mahdi

doi:10.1016/j.atherosclerosis.2010.08.062

Cited by 47 publications

(25 citation statements)

References 33 publications

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“…Male subjects with HDL-C levels below the fi fth percentile were screened for mutations in ABCA1 and LCAT ( 17,19 ), of which the functionality was assessed in previously published studies ( 17,20,21 ). For the current study, we enrolled 24 carriers of mutations in the ABCA1 gene.…”

Section: Recruitment Of Study Participantsmentioning

confidence: 99%

“…While this study showed that cholesterol delivery to the adrenals via the HDL-SRB1 pathway is important for adrenal steroidogenesis in humans, it is unclear whether plasma HDL-C levels are associated with adrenal steroidogenesis in humans. To investigate this, we assessed basal and ACTH-stimulated adrenal cortical function in males with low HDL-C due to mutations in either ATP binding cassette transporter 1 (ABCA1) ( 17 ) or lecithin:cholesterol acyltransferase (LCAT) and in subjects with low HDL-C without mutations in ABCA1/LCAT, as well as in normolipidemic controls ( 18 ). We hypothesized that in subjects with low HDL-C levels, adrenal function would be compromised irrespective of the molecular origin of the low HDL-C.…”

Section: Population Characteristicsmentioning

confidence: 99%

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High density lipoprotein as a source of cholesterol for adrenal steroidogenesis: a study in individuals with low plasma HDL-C

Bochem¹,

Holleboom²,

Romijn³

et al. 2013

Journal of Lipid Research

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The synthesis and secretion of adrenal steroid hormones for regulating stress responses, electrolyte homeostasis, and maintenance of secondary sexual characteristics depends upon the availability of the precursor cholesterol ( 1 ). To secure a continuous cholesterol supply, the adrenal glands can synthesize cholesterol, metabolize intracellular esterifi ed cholesterol, or obtain cholesterol from circulating lipoproteins ( 1 ). Although exact data are lacking, plasma lipoproteins have been suggested to contribute more than 75% of all cholesterol required for adrenal steroidogenesis ( 2, 3 ), but the current literature gives little insight in associations between plasma lipoprotein levels and adrenal function in humans.With respect to a role for low-density lipoprotein (LDL), it has been shown that LDL receptor-defi cient patients suffering from familial hypercholesterolemia display normal urinary excretion of both 17 hydroxycorticosteroids (17-OHCS) and 17 ketogenic steroid metabolites (17-KS) indicative of unaffected adrenal function ( 4, 5 ). In addition, low or absent LDL cholesterol (LDL-C) in carriers of one or two defective APOB alleles respectively did not affect basal adrenal function either ( 6 ). Combined this suggests that LDL is probably not playing a major role in delivering cholesterol for steroid hormone production in humans. Associations with HDL cholesterol (HDL-C) have thus far only been studied in critically ill patients. In one Abstract Few studies have addressed the delivery of lipoprotein-derived cholesterol to the adrenals for steroid production in humans. While there is evidence against a role for low-density lipoprotein (LDL), it is unresolved whether high density lipoprotein (HDL) contributes to adrenal steroidogenesis. To study this, steroid hormone profi les in urine were assessed in male subjects suffering from functional mutations in ATP binding cassette transporter A1 (ABCA1) (n = 24 ), lecithin:cholesterol acyltransferase (LCAT) (n = 40), as well as in 11 subjects with low HDL cholesterol (HDL-C) without ABCA1/LCAT mutations. HDL-C levels were 39% lower in the ABCA1, LCAT, and low HDL-C groups compared with controls (all P < 0.001). In all groups with low HDL-C levels, urinary excretion of 17-ketogenic steroids was reduced by 33%, 27%, and 32% compared with controls (all P < 0.04). In seven carriers of either type of mutation, adrenocorticotropic hormone (ACTH) stimulation did not reveal differences from normolipidemic controls. In conclusion, this study shows that basal but not stimulated corticosteroid metabolism is attenuated in subjects with low HDL-C, irrespective of its molecular origin. These fi ndings lend support to a role for HDL as a cholesterol donor for basal adrenal steroidogenesis in humans.

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Section: Recruitment Of Study Participantsmentioning

confidence: 99%

Section: Population Characteristicsmentioning

confidence: 99%

High density lipoprotein as a source of cholesterol for adrenal steroidogenesis: a study in individuals with low plasma HDL-C

Bochem¹,

Holleboom²,

Romijn³

et al. 2013

Journal of Lipid Research

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“…Heterozygous mutations are known to cause familial HDL deficiency. A number of recent publications (Candini et al 2010;Alrasadi et al 2006;Berge and Leren 2010) reported patients with low HDL carrying novel heterozygous mutations in their ABCA1 gene. The patient presented here did not have any corneal lesions, hepatosplenomegaly, or peripheral neuropathy.…”

Section: Discussionmentioning

confidence: 99%

A Non-classical Presentation of Tangier Disease with Three ABCA1 Mutations

et al. 2011

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“…Also in individuals that were referred to the clinic because of extreme levels of HDL cholesterol, resequencing studies of candidate genes only provided satisfying clues in a minority of the subjects studied (Candini et al 2010;Holleboom et al 2011a, b;Kiss et al 2007). It may be noted, however, that most studies conducted thus far focused only on APOAI, LCAT, and ABCA1 leaving ample room for large-effect variants in other genes.…”

Section: Missing Heritabilitymentioning

confidence: 99%

Beyond the Genetics of HDL: Why Is HDL Cholesterol Inversely Related to Cardiovascular Disease?

Kuivenhoven

Groen

2014

Handbook of Experimental Pharmacology

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Identification and characterization of novel loss of function mutations in ATP-binding cassette transporter A1 in patients with low plasma high-density lipoprotein cholesterol

Cited by 47 publications

References 33 publications

High density lipoprotein as a source of cholesterol for adrenal steroidogenesis: a study in individuals with low plasma HDL-C

High density lipoprotein as a source of cholesterol for adrenal steroidogenesis: a study in individuals with low plasma HDL-C

A Non-classical Presentation of Tangier Disease with Three ABCA1 Mutations

Beyond the Genetics of HDL: Why Is HDL Cholesterol Inversely Related to Cardiovascular Disease?

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