Lecithin:Cholesterol Acyltransferase: From Biochemistry to Role in Cardiovascular Disease

LCAT STRUCTURE AND FUNCTION

Cholesterol HDL & CETP

Lcat and free cholesterol

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In addition to its function in HDL metabolism, LCAT was believed to be an important driving force behind macrophage reverse cholesterol transport RCT and, therefore, has been a subject of great interest in cardiovascular research since its discovery in Although half a century has passed, the importance of LCAT for atheroprotection is still under intense debate. This review provides a comprehensive overview of the insights that have been gained in the past 50 years on the biochemistry of LCAT, the role of LCAT in lipoprotein metabolism and the pathogenesis of atherosclerosis in animal models, and its impact on cardiovascular disease in humans.

Subsequent work by Glomset led in to the identification of the lecithin: Four years later, Glomset identified LCAT as an important driving force behind the reverse cholesterol transport RCT pathway 3lcat and free cholesterol, a process that describes the HDL-mediated removal of excess cholesterol from macrophages in the arterial wall and subsequent delivery to the liver for biliary excretion.

Interest in the enzyme increased even further when in the first family with three sisters with familial LCAT deficiency was described 4.

To date, approximately 60 isolated cases and 70 small families with partial or complete LCAT deficiency have been described with 86 different molecular defects in the LCAT gene 5 http: In addition, numerous animal models lacking or overexpressing LCAT, including mice 6 — 10hamsters 11rabbits 12and monkeys 13 have been generated to gain better insight in the complex role of LCAT in modulating lipoprotein metabolism, RCT, and atherosclerosis.

The human LCAT gene is localized in the q21—22 region of chromosome It consists of 6 exons separated by 5 introns and encompasses a total of 4. Init was sequenced and cloned for the first time 16 The gene encodes for a polypeptide chain, consisting of amino acid residues with an apparent molecular mass of approximately 60 kDa. The biological significance of the two O-glycosylation sites is largely unclear. Site-directed mutagenesis studies in transfected COS-6 cells by substitution of Asn with Thr showed that N-linked glycosylation at Asn is indispensible for secretion of active LCAT, whereas Asn84 is critical for its full activity but not for intracellular processing In another study by Karmin and colleagues, the effect of substitution of the Asn residues with Gln was investigated in COS-1 cells These studies showed that glycosylation at all four sites is required to generate the full-size mature LCAT protein, but deletion of only one of the N-linked glycosylation sites does not affect intracellular processing and secretion.

The pattern of N-linked glycosylation, however, has profound effects on the catalytic activity of the enzyme. By use of selective chemical modification and stoichiometric analysis, it was shown that a single serine and a single histidine mediate lecithin cleavage and that the two free cysteines participate as transient fatty acyl acceptors in cholesterol esterification 24 — The first structural model of LCAT was proposed by Yang and colleagues in based upon the primary structure, chemical modification, homology with other proteins, and enzymatic assays Recently, using a combination of several new and improved fold-recognition methods, Holleboom and colleagues confirmed this model with, according to the new protein nomenclature, residues Ser, Asp, lcat and free cholesterol, and His forming the catalytic triad of LCAT LCAT contains six cysteine residues, of which four are located at the active site of the protein and are used to form two disulfide bridges Cys50—Cys74 and Cys—Cys 27 The human LCAT protein is synthesized primarily by the liver, lcat and free cholesterol, although it is also expressed in small amounts in the testes and in astrocytes in the brain, where it is involved in the esterification of cholesterol in glia-derived apoE-containing lipoproteins 152734 The half-life of human LCAT in plasma has been estimated to be 4—5 days 37 LCAT reversibly binds to lipoproteins and is primarily found on HDL, which likely prevents its rapid clearance from the circulation ApoAI is the most potent activator of LCAT, which enables it to convert free cholesterol into cholesteryl esters on HDL by a transesterification reaction involving the transfer of a fatty acid at the sn -2 position of phosphatidylcholine or lecithin to the free hydroxyl group of cholesterol 15 During this reaction, lecithins are converted into lysophosphatidylcholines, lcat and free cholesterol.

The transfer process occurs in multiple steps. The conformation of these apoAI complexes is affected by the fluidity of the lipid bilayer 40 The second step involves the cleavage of the sn headaches and dizziness after stopping lexapro ester bond of lcat and free cholesterol, leading to the release of a fatty acyl This step is mediated by the phospholipase activity of LCAT and depends on the lecithin composition Two distinct types of LCAT activity can be distinguished: Already inGlomset identified Popcorn and weight loss as an important driving force behind the RCT pathway 3a process that describes the HDL-mediated removal of excess cholesterol from peripheral tissues, including macrophages from the arterial wall, and subsequent delivery to the liver for biliary excretion Fig, lcat and free cholesterol.

LCAT functions potentially affecting the pathogenesis of cardiovascular disease. LCAT is considered an important driving force behind the RCT pathway, a process that describes the HDL-mediated removal of excess cholesterol from peripheral tissues, including macrophages in the arterial wall, and subsequent delivery to the liver for biliary excretion.

Upon esterification of cholesterol in HDL, LCAT maintains the gradient of free cholesterol between the cellular membrane and the surface of the HDL particle, which is thought to generate a continuous flow of cholesterol from the cell to lipoproteins and prevent the transfer of cholesterol back to the cell. In addition to its essential role in the first step of the RCT pathway, LCAT is suggested to enhance the delivery of cholesterol to the liver.

Furthermore, LCAT directly or indirectly interferes with several other physiological processes that might affect the development of atherosclerosis, including HDL antioxidant function by hydrolyzing oxidized phospholipids in oxidized LDL oxLDLadrenal lcat and free cholesterol, insulin sensitivity and protection against obesity, and platelet function. The first step of the RCT pathway involves production of apoAI in the liver or intestine that is then released into the plasma Interaction with ATP-binding cassette transporter ABC A1 on primarily the liver and intestine induces the formation of nascent discoidal HDL ndHDL particles that can stimulate cholesterol efflux from macrophages in the arterial wall 47 Upon further enrichment of the HDL particles with cholesteryl ester, they are transformed into larger HDL 2 particles This might be a direct effect lcat and free cholesterol the fact that LCAT is subject to product inhibition 45but it has also been suggested that sphingomyelin enrichment of HDL prevents binding of LCAT to the lipoprotein 49 Importantly, upon esterification of cholesterol in HDL, LCAT maintains the gradient of free cholesterol between the cellular membrane and the surface of the HDL particle, which is thought to generate a continuous flow of cholesterol from the cell to lipoproteins and prevent the transfer of cholesterol back to the cell 54 — Importantly, it is also postulated that the effect of LCAT on the flux of cholesterol may depend both on the type and metabolic status of the cells, and on the environment of HDL in the extracellular medium Therefore, in addition to its essential role in the first step of the RCT pathway, LCAT is lcat and free cholesterol to enhance the delivery of cholesterol to the liver Fifth, serum from carriers of LCAT gene mutations has the same capacity as control serum to decrease the cholesterol content of cholesterol-loaded macrophages due to a lcat and free cholesterol cholesterol efflux capacity via ABCA1 62 Finally and most importantly, the role of LCAT as an atheroprotective factor is under debate.

LCAT also transesterifies and hydrolyzes platelet-activating factor and oxidized phospholipids with long chains in the sn -2 position lcat and free cholesterol — Isolated human HDL contains some 50 different proteins 69 and a complex range of small peptides However, because oxidation of plasma lipoproteins is an important event in the formation of atherogenic particles, impaired LCAT lcat and free cholesterol is anticipated to induce the pathogenesis of atherosclerosis.

Recently, evidence was provided that SR-BI-mediated uptake of cholesterol from HDL by the adrenal is essential to acquire cholesterol for the production of glucocorticoids, both in mice and in humans 71 As LCAT is not expressed in adrenal 27the most likely cause for the reduced lipid content of the adrenal is the severe depletion of plasma HDL cholesterol.

In humans, LDL receptor-mediated uptake of LDL was long considered the primary pathway for delivery lcat and free cholesterol cholesterol from the circulation to the adrenal. However, recently we found that subjects with an SR-BI c. Because glucocorticoids have important anti-inflammatory properties, altered glucocorticoid production in response to inflammation in the arterial wall might influence the progression of the disease.

It is currently unknown whether LCAT-deficient patients suffer more frequently from adrenal insufficiency. However, lcat and free cholesterol, carriers of LCAT mutations display lower total urinary ketogenic steroids and hydroxycorticoids LCAT deficiency in mice is associated with enhanced insulin sensitivity 74 Furthermore, recently it was reported that LCAT-deficient mice, especially females, are protected against high-fat high-sucrose HFHS diet-induced obesity These protective metabolic phenotypes are associated with protection against diet-induced hepatic and adipocyte endoplasmic reticulum ER stress, but the mechanistic link with the enzymatic action of LCAT needs further investigation.

An early study showed that both fractional and molar LCAT rates were positively correlated with obesity in lisinopril and tylenal but not in men However, another more recent study found increased plasma LCAT in obese individuals of both sexes Furthermore, the plasma LCAT activity level was shown to be positively related to lcat and free cholesterol resistance in association with a higher body mass index BMI in a group of 32 Dutch men Considering that obesity is the epidemic of the twenty-first century and is a prominent risk factor for cardiovascular disease, the link between LCAT, insulin resistance, and obesity warrants further investigation.

Acute coronary events are not the result of progressive growth of the lesion but, rather, of lesion disruption and superimposed thrombus formation in which platelets are key elements. Platelets from two LCAT-deficient patients did not show alterations in the cholesterol: In agreement, one patient showed increased platelet thrombin-induced aggregation responses, but aggregation in another was decreased.

The effects of LCAT deficiency on platelet activation are thus inconclusive, and studies in more patients and characterizing the different aspects of platelet function, including, for example, aggregation responses to different agonists and adhesion under flow, are awaited. In summary, in addition to its role in RCT, LCAT directly or indirectly interferes with several other physiological processes that might affect the development of atherosclerosis Fig.

Individuals with deleterious mutations on both alleles present with HDL deficiency, whereas heterozygotes typically have HDL cholesterol levels that are half of normal HDL cholesterol 82 Two important LCAT deficiency syndromes can be distinguished: FLD was reported for the first time in in a Norwegian family. In this family, three adult sisters showed extremely low plasma LCAT activity, reduced levels of cholesteryl esters, and reduced plasma LCAT concentration 4.

The clinical features included proteinuria, normochromic anemia, corneal opacity 84and turbid milky plasma. Furthermore, lcat and free cholesterol, foam cells were found in the bone marrow and kidney, and lipid alterations were found in the post menopausal estradiol levels and periods Years later, lcat and free cholesterol, it was established that homozygosity for a single nucleotide substitution in codon of exon 6 in the gene, leading to the exchange of a methionine ATG for a lysine residue AAGwas responsible for the LCAT deficiency in this family In vitro experiments showed that this mutation led to the production of a fully inactive LCAT enzyme Important clinical features are corneal opacification, lcat and free cholesterol, mild anemia, and progressive loss of renal function Adapted from Hill The latter have LCAT with a reduced ability to esterify cholesterol bound to HDL, but lcat and free cholesterol of cholesterol bound to other lipoproteins e.

In lcat and free cholesterol, Kuivenhoven et al. For the in vivo classification, five criteria were proposed: For the in vitro experiments, two criteria were proposed: The classification system describes five classes. The first class contains null mutations of the LCAT gene. This means that patients in this class display a total loss of catalytic activity of LCAT and that they have the clinical phenotype of FLD.

The second class contains missense mutations that cause complete or nearly complete loss of catalytic activity of the LCAT gene. The third class contains both missense mutations and minor deletions in the LCAT gene that are lcat and free cholesterol for an intermediate phenotype, meaning that there is either partial loss of activity against LDL or combined partial loss of activity against both HDL and LDL.

The fourth class contains the mutations responsible for the typical symptoms of the FED syndrome, lcat and free cholesterol. This class thus includes missense mutations that result in specific loss of activity against HDL analogs, but activity against LDL or other apoB-containing lipoproteins is preserved. The fifth class contains three mutations that the group of Kuivenhoven et al. LCAT deficiency is a rare disorder.

InHovig and Gjone demonstrated lipid deposition in renal arteries and veins of patients with FLD Furthermore, the lcat and free cholesterol contained numerous lipid-laden cells that are assumed to be partly responsible for the splenomegaly found in FLD patients. InCarlson showed that FED patients did not suffer from premature atherosclerosis in spite of the extremely low HDL cholesterol levels This was surprising, as FED patients have very low levels of HDL, and it thus was expected that these patients would have an increased risk for atherosclerosis.

Four years later, it was demonstrated that patients with atherosclerosis one- to three-vessel disease had increased LCAT levels compared with healthy controls clinical out-patients or hospital personnel and patients without atherosclerosis zero-vessel disease Furthermore, LCAT activity was augmented with increased severity of coronary atherosclerosis. The results of this study suggest that increased, rather than decreased, plasma LCAT activity is characteristic of coronary atherogenesis.

Since then, lcat and free cholesterol, the lcat and free cholesterol of LCAT in the pathogenesis of atherosclerosis has been under debate. Strikingly, in several of the studies no differentiation was made between the phenotypic differences of FED and FLD patients, lcat and free cholesterol.

 

Lcat and free cholesterol

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