LCAT deficiency: molecular genetics, lipid/lipoprotein phenotype and atherosclerosis

Calabresi, Laura; Moleri, Elsa; Franceschini, Guido

doi:10.2217/17460875.1.3.241

Cited by 2 publications

(1 citation statement)

References 28 publications

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“…Almost all described mutations fall in the coding region of LCAT gene, with only two in intronic sequences. The majority of described genetic variations are loss-of-function mutations leading to proteins with total or partial lack of LCAT activity [17]; among these, five are nonsense mutations, 75 missense mutations, two deletions, three insertions and 13 frameshift. Mutations are spread throughout the LCAT gene, often in regions not involved in catalytic site of the enzyme and likely important to maintain LCAT structure.…”

Section: Lcat Deficiencymentioning

confidence: 99%

Familial LCAT deficiency: from pathology to enzyme replacement therapy

Ossoli

Lucca

Boscutti

et al. 2015

Clinical Lipidology

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Lecithin:cholesterol acyltransferase (LCAT) synthesizes most of the plasma cholesteryl esters, and plays a major role in HDL metabolism. Mutations in the LCAT gene cause two syndromes, familial LCAT deficiency and fish-eye disease, both characterized by severe alterations in plasma lipoprotein profile. Renal disease is the major cause of morbidity and mortality in familial LCAT deficiency cases, but an established therapy is not currently available. The present therapy of LCAT deficiency is mainly aimed at correcting the dyslipidemia associated with the disease and at delaying evolution of chronic nephropathy. LCAT deficiency represents a candidate disease for enzyme replacement therapy. In vitro and in vivo studies proved the efficacy of recombinant human LCAT in correcting dyslipidemia, and recombinant human LCAT is presently under development.Lecithin:cholesterol acyltransferase (LCAT) enzyme is a monomeric glycoprotein that is responsible for the production of cholesteryl esters (CE) in human plasma and plays a critical role in maturation of HDL [1]. LCAT gene is localized on chromosome 16 (region 16q22) and the coding sequence, approximately 1.5 Kb, contains six exons. LCAT mRNA is found mainly in the liver, but it can also be found in smaller amount in brain and testis [2]. The mature form of LCAT is a glycoprotein of 416 residues with 67 kDa of molecular mass; the tertiary structure of the protein has recently been solved in a lowresolution model [3] that confirms the close homology with lysosomal PLA2 already described [4]. It contains three domains, a α/β-hydrolase fold, a cap domain and a membrane-binding domain. LCAT is found in human plasma in low concentration (about 5 μg/ml) preferentially bound to HDL and also to LDL particles. LCAT enzyme activity and protein concentration are highly correlated, and they may vary in according to age, gender, smoking and alimentary habits [5].Phospholipase and acyltransferase activities are both described as enzymatic activities of LCAT that catalyzes the formation of CE by cleavage of the fatty acid in sn-2 position of lecithin and transfer of the residue onto Ser181; then, the fatty acid is transesterified to the free 3-b hydroxyl group of cholesterol [2]. These reactions can occur in both HDL and LDL particles with activities called respectively α-and β-LCAT activity. The large part of CE circulating in human plasma is generated by α-LCAT activity on HDL that represent the preferential substrate for the enzyme; furthermore apoA-I is the main cofactor of LCAT in plasma [2]. The β-LCAT activity consists in cholesterol esterification within apoB-containing lipoproteins with apoE as cofactor [6].LCAT plays a crucial role in the HDL maturation process. Small discoidal pre-β-HDL are generated through the interaction of the ABCA1 transporter, located on the cell membrane, with lipid-poor apoA-I, and then LCAT esterifies cholesterol to form CE, more hydrophobic, which migrate into the

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Section: Lcat Deficiencymentioning

confidence: 99%

Familial LCAT deficiency: from pathology to enzyme replacement therapy

Ossoli

Lucca

Boscutti

et al. 2015

Clinical Lipidology

Self Cite

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Measurement of Lecithin–Cholesterol Acyltransferase Activity with the Use of a Peptide-Proteoliposome Substrate

Vaisman

Remaley

2013

Methods in Molecular Biology

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Lecithin-cholesterol acyltransferase (LCAT) is the major enzyme responsible for the esterification of free cholesterol on plasma lipoproteins, which is a key step in the reverse cholesterol transport pathway. The measurement of plasma LCAT activity not only is important in the diagnosis of patients with genetic or acquired LCAT deficiency but is also valuable in calculating cardiovascular risk, as well as in research studies of lipoprotein metabolism. In this chapter, we describe a convenient LCAT assay based on the use of an apoA-I mimetic peptide. The proteoliposome substrate used in this assay for LCAT is easily made with the peptide and can be stored by deep freezing without significant loss of activity.

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LCAT deficiency: molecular genetics, lipid/lipoprotein phenotype and atherosclerosis

Cited by 2 publications

References 28 publications

Familial LCAT deficiency: from pathology to enzyme replacement therapy

Familial LCAT deficiency: from pathology to enzyme replacement therapy

Measurement of Lecithin–Cholesterol Acyltransferase Activity with the Use of a Peptide-Proteoliposome Substrate

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