Functional Lecithin: Cholesterol Acyltransferase Is Not Required for Efficient Atheroprotection in Humans

Calabresi, Laura; Baldassarre, Damiano; Castelnuovo, S.; Conca, Paola; Bocchi, Leonardo; Candini, C.; Frigerio, B.; Amato, Mauro; Sirtori, Cesare R.; Alessandrini, Paola; Arca, Marcello; Boscutti, Giuliano; Cattin, Luigi; Gesualdo, Loreto; Sampietro, Tiziana; Vaudo, Gaetano; Veglia, Fabrizio; Calandra, Sebastiano; Franceschini, Guido

doi:10.1161/circulationaha.108.818143

Cited by 54 publications

(18 citation statements)

References 30 publications

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“…The homozygous carriers had only minimal increases in IMT and no plaques, whereas some IMT abnormalities were observed in four of the seven heterozygotes 48) . In accordance with these data, a study conducted in 2009 in a larger number of carriers from 13 Italian families clearly showed that functional LCAT is not required for efficient atheroprotection 49) . In this study, carotid IMT was measured in 12 carriers of two mutant LCAT alleles, in 28 carriers of one mutant LCAT allele, and in 80 healthy age -gender-matched controls.…”

Section: Carriers Of Genetic Lcat Deficiencysupporting

confidence: 58%

Role of LCAT in Atherosclerosis

Ossoli

Simonelli

Vitali

et al. 2016

J Atheroscler Thromb

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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 Deficiencysupporting

confidence: 58%

Role of LCAT in Atherosclerosis

Ossoli

Simonelli

Vitali

et al. 2016

J Atheroscler Thromb

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“…More than 86 defects in LCAT gene have been identified (10), and for several decades conflicting findings on the association of LCAT deficiency with atherosclerosis have been reported in humans and experimental animals (7,39). Thus, some (15,40) but not all studies (16), have found that reduced LCAT activity is associated with increased cIMT and with the presence of CAD (10). A recent study reported that compared with 80 matched healthy controls, 12 individuals with two loss-of-function LCAT mutations and 28 heterozygous carriers with one mutation did not have increased cIMT as compared to 80 matched healthy controls, and instead there was a strong suggestion for a gene dose-dependent reduction in cIMT (16).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, some (15,40) but not all studies (16), have found that reduced LCAT activity is associated with increased cIMT and with the presence of CAD (10). A recent study reported that compared with 80 matched healthy controls, 12 individuals with two loss-of-function LCAT mutations and 28 heterozygous carriers with one mutation did not have increased cIMT as compared to 80 matched healthy controls, and instead there was a strong suggestion for a gene dose-dependent reduction in cIMT (16). These findings suggest that LCAT deficiency is not associated with increased cardiovascular risk.…”

Section: Discussionmentioning

confidence: 99%

“…Atherosclerosis susceptibility has been extensively investigated in FED and FLD patients (10). Studies assessing the association between the inherited LCAT functional defect and CAD have been limited to measurements of only some variables, such as the HDL subclasses (11)(12) size (9) and function (13)(14), apoA-I and apoA-II plasma concentrations (9), inflammation (15), and carotid intima-media-thickness (cIMT) (15)(16). This study aimed to provide more information on the LCAT-deficient state and its association with CAD by describing LDL susceptibility to oxidation in addition to the above-mentioned variables, in a LCAT-deficient patient with severe premature CAD and his nuclear family.…”

Section: Introductionmentioning

confidence: 99%

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Premature and severe cardiovascular disease in a Mexican male with markedly low high-density-lipoprotein-cholesterol levels and a mutation in the lecithin:cholesterol acyltransferase gene: A family study

Posadas-Sánchez

Posadas‐Romero

Ocampo-Arcos

et al. 2014

International Journal of Molecular Medicine

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Abstract. Epidemiological and clinical studies have shown that a low plasma high-density lipoprotein cholesterol (HDL-C) level is a strong predictor of cardiovascular disease (CVD). Lecithin:cholesterol acyltransferase (LCAT) is a key enzyme in the formation, maturation and function of HDL. Therefore impaired LCAT function may enhance atherosclerosis because of defective cholesterol transport. In this study, we examined a 34-year old LCAT-deficient patient and eight first-degree family members. There was a strong family history for CVD and type 2 diabetes mellitus (DM2). The proband was found homozygous for a previously reported LCAT gene mutation (Thr37Met). A sister and two sons of the proband were heterozygous for the same mutation. The proband had DM2 and showed severe multivessel coronary artery disease, corneal opacification and extremely low HDL-C levels. Large HDL particles were absent while small HDL particles were increased. The HDL of the patient had a reduced ability to promote cell cholesterol efflux, and the low-density lipoproteins (LDL) were more susceptible to oxidation. Among his family members, two heterozygotes and one non-carrier had early carotid or coronary atherosclerosis. In conclusion, as the increased LDL oxidability and structural and functional abnormalities of HDL particles have been reported in patients with obesity and diabetes, the results suggested that the adverse coronary risk profile, and not being LCAT deficient, may be responsible for the CVD found in our proband, and for the early atherosclerosis observed in the two heterozygotes and in the wild-type family members.

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“…Es gilt heute als fraglich, ob eine niedrige Konzentration der HDL ursächlich für Atherosklerose ist. [12]. Bei einigen Patienten wird der Verlauf der Erkrankung von der sich entwickelnden Niereninsuffizienz bestimmt.…”

Section: Dyslipoproteinämien Mit Niedriger Konzentration Der Hdlunclassified