Familial lecithin-cholesterol acyltransferase deficiency: Biochemical characteristics and molecular analysis of a new LCAT mutation in a Polish family

Idzior−Waluś, Barbara; Sieradzki, Jacek; Kostner, Gert M.; Małecki, Maciej; Klupa, Tomasz; Wesołowska, Teresa; Rostworowski, W; Hartwich, J.; Waluś, Małgorzata; Kieć, Aldona Dembińska; Naruszewicz, Marek

doi:10.1016/j.atherosclerosis.2005.06.022

Cited by 11 publications

(12 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Homozygotes or compound heterozygotes for LCAT mutations all presented with the clinical phenotype of fish eye disease (56)(57)(58). Tangier disease patients were previously described (59,60) and have deleterious mutations on both alleles.…”

Section: Human Studiesmentioning

confidence: 99%

ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice

Murphy¹,

Akhtari²,

Tolani³

et al. 2011

J. Clin. Invest.

451

532

View full text Add to dashboard Cite

Leukocytosis is associated with increased cardiovascular disease risk in humans and develops in hypercholesterolemic atherosclerotic animal models. Leukocytosis is associated with the proliferation of hematopoietic stem and multipotential progenitor cells (HSPCs) in mice with deficiencies of the cholesterol efflux-promoting ABC transporters ABCA1 and ABCG1 in BM cells. Here, we have determined the role of endogenous apolipoprotein-mediated cholesterol efflux pathways in these processes. In Apoe -/-mice fed a chow or Western-type diet, monocytosis and neutrophilia developed in association with the proliferation and expansion of HSPCs in the BM. In contrast, Apoa1 -/-mice showed no monocytosis compared with controls. ApoE was found on the surface of HSPCs, in a proteoglycan-bound pool, where it acted in an ABCA1-and ABCG1-dependent fashion to decrease cell proliferation. Accordingly, competitive BM transplantation experiments showed that ApoE acted cell autonomously to control HSPC proliferation, monocytosis, neutrophilia, and monocyte accumulation in atherosclerotic lesions. Infusion of reconstituted HDL and LXR activator treatment each reduced HSPC proliferation and monocytosis in Apoe -/-mice. These studies suggest a specific role for proteoglycanbound ApoE at the surface of HSPCs to promote cholesterol efflux via ABCA1/ABCG1 and decrease cell proliferation, monocytosis, and atherosclerosis. Although endogenous apoA-I was ineffective, pharmacologic approaches to increasing cholesterol efflux suppressed stem cell proliferative responses.

show abstract

Section: Human Studiesmentioning

confidence: 99%

ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice

Murphy¹,

Akhtari²,

Tolani³

et al. 2011

J. Clin. Invest.

451

532

View full text Add to dashboard Cite

show abstract

“…The diagnosis was finally confirmed by a marked decrease in LCAT activity and absence of LCAT protein. Genetic analyses confirmed a presence of Val309Met mutation in exon 6 of LCAT gene [14].…”

Section: Description Of Patientsmentioning

confidence: 67%

“…The plasma lipid concentration of patients with homozygous familial LCAT are shown in Table 1. In both patients Lp-X was present [14]. The diagnosis was finally confirmed by a marked decrease in LCAT activity and absence of LCAT protein.…”

Section: Description Of Patientsmentioning

confidence: 76%

Corticosteroid treatment of kidney disease in a patient with familial lecithin-cholesterol acyltransferase deficiency

et al. 2011

Self Cite

View full text Add to dashboard Cite

Familial lecithin-cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disorder of lipid metabolism, characterised by low plasma HDL cholesterol, proteinuria, haemolytic anaemia and corneal opacities. Usually renal disease progresses during the third decade of life to renal failure; however the pathogenesis of renal disease is not well understood. In this study we describe treatment of renal disease in two siblings with FLD. The proband WX at the age of 31 years presented proteinuria and ankle oedema during her third pregnancy. Diagnosis of FLD was based on a renal biopsy with characteristic serpiginous fibrillar deposits under electron microscopy, markedly decreased HDL cholesterol, esterified cholesterol levels and LCAT activity, confirmed by molecular analysis. After 3 years her proteinuria increased and she received an ACE inhibitor to which she responded well. During further increases of proteinuria she additionally received methylprednisolone and her proteinuria decreased. This long-term observation indicates the efficacy of corticosteroids and renin-angiotensin-aldosterone system blockers in the treatment of proteinuria in patients with FLD. The results suggest the role of inflammatory processes as well as dyslipidemia in the pathogenesis of glomerular disorders in LCAT-deficient patients.

show abstract

“…One patient with FED was homozygous for the p.T123I mutation 34 (which is now annotated p.T147I, including the 24-aa leader sequence, following the guidelines of the Human Genome Variation Society to describe mutations), the other compound heterozygous for p.T147I and p.V333M. 35 The patients with FLD were homozygous for either p.C337Y 36 or p.T345M. 37 In addition, 63 heterozygous carriers of LCAT gene mutations and 63 unaffected family controls participated in the study.…”

Section: Resultsmentioning

confidence: 99%

Lipid Oxidation in Carriers of Lecithin:Cholesterol Acyltransferase Gene Mutations

Holleboom

Daniil

et al. 2012

ATVB

View full text Add to dashboard Cite

Objective Lecithin:cholesterol acyltransferase (LCAT) has been shown to play a role in the depletion of lipid oxidation products, but this has so far not been studied in humans. In this study, we investigated processes and parameters relevant to lipid oxidation in carriers of functional LCAT mutations. Methods and Results In 4 carriers of 2 mutant LCAT alleles, 63 heterozygotes, and 63 family controls, we measured activities of LCAT, paraoxonase 1, and platelet-activating factor-acetylhydrolase; levels of lysophosphatidylcholine molecular species, arachidonic and linoleic acids, and their oxidized derivatives; immunodetectable oxidized phospholipids on apolipoprotein (apo) B–containing and apo(a)-containing lipoproteins; IgM and IgG autoantibodies to malondialdehyde-low-density lipoprotein and IgG and IgM apoB-immune complexes; and the antioxidant capacity of high-density lipoprotein (HDL). In individuals with LCAT mutations, plasma LCAT activity, HDL cholesterol, apoA-I, arachidonic acid, and its oxidized derivatives, oxidized phospholipids on apo(a)-containing lipoproteins, HDL-associated platelet-activating factor-acetylhydrolase activity, and the antioxidative capacity of HDL were gene-dose–dependently decreased. Oxidized phospholipids on apoB-containing lipoproteins was increased in heterozygotes (17%; P<0.001) but not in carriers of 2 defective LCAT alleles. Conclusion Carriers of LCAT mutations present with significant reductions in LCAT activity, HDL cholesterol, apoA-I, platelet-activating factor-acetylhydrolase activity, and antioxidative potential of HDL, but this is not associated with parameters of increased lipid peroxidation; we did not observe significant changes in the oxidation products of arachidonic acid and linoleic acid, immunoreactive oxidized phospholipids on apo(a)-containing lipoproteins, and IgM and IgG autoantibodies against malondialdehyde-low-density lipoprotein. These data indicate that plasma LCAT activity, HDL-associated platelet-activating factor-acetylhydrolase activity, and HDL cholesterol may not influence the levels of plasma lipid oxidation products.

show abstract

Familial lecithin-cholesterol acyltransferase deficiency: Biochemical characteristics and molecular analysis of a new LCAT mutation in a Polish family

Cited by 11 publications

References 30 publications

ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice

ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice

Corticosteroid treatment of kidney disease in a patient with familial lecithin-cholesterol acyltransferase deficiency

Lipid Oxidation in Carriers of Lecithin:Cholesterol Acyltransferase Gene Mutations

Contact Info

Product

Resources

About