Cholesterol Acyltransferase Gene Mutations Have Accelerated Atherogenesis as Assessed by Carotid 3.0-T Magnetic Resonance Imaging

Duivenvoorden, Raphaël; Holleboom, Adriaan G.; Bogaard, Bas van den; Nederveen, Aart J.; Groot, Eric de; Hutten, Barbara A.; Schimmel, Alinda W.M.; Hovingh, G. Kees; Kastelein, John J.P.; Kuivenhoven, Jan Albert; Stroes, Erik S.G.

doi:10.1016/j.jacc.2010.11.092

Cited by 56 publications

(37 citation statements)

References 27 publications

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“…Carriers mutations leading to FLD. Results clearly showed that LCAT deficient carriers had a greater increase in the thickness of carotid artery walls and 32% increase of plaque component compared with family controls 51) . In the same population, arterial stiffness that represents a strong and independent predictor of cardiovascular events was assessed by the measurement of carotid-femoral pulse wave velocity 52) .…”

Section: Carriers Of Genetic Lcat Deficiencymentioning

confidence: 88%

“…Carriers of two mutant LCAT alleles had greater average carotid IMT than controls, but the low number and completely different age distribution did not provide adequate power for statistical evaluation 50) . Supporting the evidence that low LCAT levels are associated with increased carotid IMT, in 2011, the carotid artery wall thickening was measured by 3.0-T carotid magnetic resonance imaging (MRI) technique in two homozygous and 38 heterozygous carriers from 14 Dutch families 51) . In this study, more than 80% of carriers were classified as FED, whereas less than 20% had…”

Section: Subjects At High Cardiovascular Riskmentioning

confidence: 98%

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Role of LCAT in Atherosclerosis

Ossoli

Simonelli

Vitali

et al. 2016

JAT

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Lecithin:cholesterol acyltransferase (LCAT) is the only enzyme capable of esterifying cholesterol in plasma, thus determining the maturation of high-density lipoproteins. Because it maintains an unesterified cholesterol gradient between peripheral cells and extracellular acceptors, for a long time, LCAT has been considered as a key enzyme in reverse cholesterol transport. However, despite the fact that it has been more than 50 years since the identification of LCAT, the role of this enzyme in the pathogenesis of atherosclerosis is still debated. A number of studies have been conducted in different animal models, with contradictory results. Studies in humans, in particular in the general population, in subjects at high cardiovascular risk, and in carriers of genetic LCAT deficiency in an excellent model to evaluate the correlation between the reduction of LCAT activity and atherosclerosis also gave conflicting results. This review provides a comprehensive overview of the controversial findings obtained in animals and humans, strengthening the necessity of further investigation to establish how LCAT could be regulated in a promising therapeutic strategy to reduce cardiovascular risk.

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Section: Carriers Of Genetic Lcat Deficiencymentioning

confidence: 88%

Section: Subjects At High Cardiovascular Riskmentioning

confidence: 98%

Role of LCAT in Atherosclerosis

Ossoli

Simonelli

Vitali

et al. 2016

JAT

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“…In this study, 40 subjects (38 heterozygotes and 2 homozygotes) with mutations in the gene for LCAT were compared with 40 controls (both family members and unrelated individuals) matched for age and cardiovascular risk factors ( 111,112 ). The carriers had 10% higher normalized wall index and 20% higher mean wall area and total wall volume.…”

Section: Lcat and Atherosclerosis In Human Studiesmentioning

confidence: 99%

Lecithin:cholesterol acyltransferase: old friend or foe in atherosclerosis?

Kunnen

Eck

2012

Journal of Lipid Research

151

119

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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%

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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Cholesterol Acyltransferase Gene Mutations Have Accelerated Atherogenesis as Assessed by Carotid 3.0-T Magnetic Resonance Imaging

Abstract: Carriers of LCAT gene mutations exhibit increased carotid atherosclerosis, indicating an increased risk of cardiovascular disease. The present findings imply that increasing LCAT activity may be an attractive target in cardiovascular prevention strategies.

Cited by 56 publications

References 27 publications

Role of LCAT in Atherosclerosis

Role of LCAT in Atherosclerosis

Lecithin:cholesterol acyltransferase: old friend or foe in atherosclerosis?

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

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