Effects of lecithin: Cholesterol acyltransferase genotypes, enzyme levels, and activity on high-density lipoprotein levels

Ağırbaşlı, Deniz; Çirakoğlu, Beyazıt; Eren, Fatih; Sumerkan, M.C.; Aksoy, Sukru; Aral, Cenk; Ağırbaşlı, Mehmet

doi:10.1016/j.jacl.2011.02.008

Cited by 7 publications

(4 citation statements)

References 31 publications

(32 reference statements)

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“…This is a middle-low frequency variant found in 4% of Chileans. As p.L393 L does not change amino acid sequence it was not possible to assess its in vitro effect in the same way as we did for p.V333 M and p.M404 V. It was previously reported a lack of association was found between p.L393 L variant with in LCAT activity or HDL-cholesterol levels [33, 34]. Surprisingly, we found a modest although significant nominal association between p.L393 L and plasma HDL-cholesterol levels in GOCS participant.…”

Section: Discussionmentioning

confidence: 97%

Identification and functional analysis of missense mutations in the lecithin cholesterol acyltransferase gene in a Chilean patient with hypoalphalipoproteinemia

et al. 2019

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Background Lecithin-cholesterol acyltransferase (LCAT) is a plasma enzyme that esterifies cholesterol in high- and low-density lipoproteins (HDL and LDL). Mutations in LCAT gene causes familial LCAT deficiency, which is characterized by very low plasma HDL-cholesterol levels (Hypoalphalipoproteinemia), corneal opacity and anemia, among other lipid-related traits. Our aim is to evaluate clinical/biochemical features of a Chilean family with a proband showing clinical signs of familial LCAT deficiency, as well as to identify and assess the functional effects of LCAT mutations. Methods An adult female proband with hypoalphalipoproteinemia, corneal opacity and mild anemia, as well as her first-degree relatives, were recruited for clinical, biochemical, genetic, in-silico and in-vitro LCAT analysis. Sequencing of exons and intron-exon boundaries was performed to identify mutations. Site-directed mutagenesis was carried out to generate plasmids containing cDNA with wild type or mutant sequences. Such expression vectors were transfected to HEK-239 T cells to asses the effect of LCAT variants in expression, synthesis, secretion and enzyme activity. In-silico prediction analysis and molecular modeling was also used to evaluate the effect of LCAT variants. Results LCAT sequencing identified rare p.V333 M and p.M404 V missense mutations in compound heterozygous state in the proband, as well the common synonymous p.L363 L variant. LCAT protein was detected in proband’s plasma, but with undetectable enzyme activity compared to control relatives. HEK-293 T transfected cells with vector expression plasmids containing either p.M404 V or p.V333 M cDNA showed detectable LCAT protein expression both in supernatants and lysates from cultured cells, but with much lower enzyme activity compared to cells transfected with the wild-type sequence. Bioinformatic analyses also supported a causal role of such rare variations in LCAT lack of function. Additionally, the proband carried the minor allele of the synonymous p.L363 L variant. However, this variant is unlikely to affect the clinical phenotype of the proband given its relatively high frequency in the Chilean population (4%) and its small putative effect on plasma HDL-cholesterol levels. Conclusion Genetic, biochemical, in vitro and in silico analyses indicate that the rare mutations p.M404 V and p.V333 M in LCAT gene lead to suppression of LCAT enzyme activity and cause clinical features of familial LCAT deficiency. Electronic supplementary material The online version of this article (10.1186/s12944-019-1045-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 97%

Identification and functional analysis of missense mutations in the lecithin cholesterol acyltransferase gene in a Chilean patient with hypoalphalipoproteinemia

et al. 2019

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“…In addition to PC metabolism, PLA2 participates in several vital pathways, including arachidonic acid metabolism, the MAPK signaling pathway, the VEGF signaling pathway and the GnRH signaling pathway. Lecithin-cholesterol acyltransferase (LCAT) is a plasma enzyme that transfers acyl groups to sterols, and it modulates the metabolism of high-density lipoprotein cholesterols, especially in subjects with low high-density lipoprotein cholesterol levels . The bacterial LCAT enzyme also catalyzes the reactions of phospholipase A2 and lysophospholipase .…”

Section: Discussionmentioning

confidence: 99%

“…Lecithincholesterol acyltransferase (LCAT) is a plasma enzyme that transfers acyl groups to sterols, and it modulates the metabolism of high-density lipoprotein cholesterols, especially in subjects with low high-density lipoprotein cholesterol levels. 26 The bacterial LCAT enzyme also catalyzes the reactions of phospholipase A2 and lysophospholipase. 27 The low expression of LCAT during FHF could cause the low acylation of cholesterol, which would be consistent with a previous report.…”

Section: ■ Discussionmentioning

confidence: 99%

Return of the Metabolic Trajectory to the Original Area after Human Bone Marrow Mesenchymal Stem Cell Transplantation for the Treatment of Fulminant Hepatic Failure

Xin

Hao

et al. 2012

J. Proteome Res.

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Our recent study first demonstrated that human bone marrow mesenchymal stem cell (hBMSC) transplantation could prevent death from fulminant hepatic failure (FHF) in pigs. To further clarify the metabolic mechanism of hBMSC transplantation in FHF, the plasma collected from FHF pigs that received transplantation of hBMSCs was examined using metabolic analysis to identify the key molecular markers that regulate recovery. The results showed that obvious metabolic disturbance occurred during FHF, whereas the hBMSC transplantation group showed less severe liver injury. The metabolic trajectory returns to its original state at week 3 following the hBMSC transplantation. In total, the concentration of 26 metabolites, including conjugated bile acids, phosphatidylcholines, lysophosphatidylcholines, fatty acids, amino acid and sphingomyelin, are significantly different between the FHF group and the hBMSC transplantation group. Moreover, the time course of changes in the metabolites corresponded with that of the biochemical and histological analyses. Real-time PCR further confirmed that the gene expression of phospholipase A1, lecithin-cholesterol acyltransferase and lysophosphatidylcholine acyltransferase 1 decreased significantly, whereas that of phospholipase A2 remained stable, which explains the decrease of the phosphatidylcholines and lysophosphatidylcholines. These novel results have revealed a metabolic mechanism for the hBMSC transplantation in FHF, which could lead to the future development of treatment strategies for stem cell therapies.

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“…Due to its functional role in RCT, it is logical that the majority of candidate gene studies have focused on HDL as the phenotypic outcome of interest. Significant associations have been detected between LCAT polymorphisms and HDL in clinical populations, but there is not substantial evidence to definitively conclude that variants in this gene strongly impact blood lipid concentrations [ 29 ].…”

Section: Genetic Contributions To Dyslipidemiamentioning

confidence: 99%

Nutrigenetic Contributions to Dyslipidemia: A Focus on Physiologically Relevant Pathways of Lipid and Lipoprotein Metabolism

2018

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Cardiovascular disease (CVD) remains the number one cause of death worldwide, and dyslipidemia is a major predictor of CVD mortality. Elevated lipid concentrations are the result of multiple genetic and environmental factors. Over 150 genetic loci have been associated with blood lipid levels. However, not all variants are present in pathways relevant to the pathophysiology of dyslipidemia. The study of these physiologically relevant variants can provide mechanistic understanding of dyslipidemia and identify potential novel therapeutic targets. Additionally, dietary fatty acids have been evidenced to exert both positive and negative effects on lipid profiles. The metabolism of both dietary and endogenously synthesized lipids can be affected by individual genetic variation to produce elevated lipid concentrations. This review will explore the genetic, dietary, and nutrigenetic contributions to dyslipidemia.

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Effects of lecithin: Cholesterol acyltransferase genotypes, enzyme levels, and activity on high-density lipoprotein levels

Cited by 7 publications

References 31 publications

Identification and functional analysis of missense mutations in the lecithin cholesterol acyltransferase gene in a Chilean patient with hypoalphalipoproteinemia

Identification and functional analysis of missense mutations in the lecithin cholesterol acyltransferase gene in a Chilean patient with hypoalphalipoproteinemia

Return of the Metabolic Trajectory to the Original Area after Human Bone Marrow Mesenchymal Stem Cell Transplantation for the Treatment of Fulminant Hepatic Failure

Nutrigenetic Contributions to Dyslipidemia: A Focus on Physiologically Relevant Pathways of Lipid and Lipoprotein Metabolism

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